Rollenhagen-Lübke2016 ReferenceWorkEntry DendriticElaborationMorphology

Dendritic Elaboration: Morphology and
Chemistry 10
€bke
Astrid Rollenhagen and Joachim H. R. Lu
Contents
Structure of Dendrites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227
Dendritic Arborization Patterns . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
Subcellular Structure of Dendrites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
Dendritic Specializations and Appendages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
Fine Structure of Dendritic Spines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
Functional Plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
Dendritic Plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
Long-Term Potentiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237
Spike-Timing-Dependent Plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Dendritic Excitability and Synaptic Plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 243
Structural Plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245
Experience Induced Structural Dendritic Plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
Sensory Deprivation, Enriched Environment and Behavioral Training . . . . . . . . . . . . . . . . . . . . 249
Hormone Induced Structural Dendritic Plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 250
Structural Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
Abstract
Dendrites (from Greek δένδρoν déndron, “tree”) are one of the major structural
elements of neurons and exhibit enormously diverse forms. They receive,
A. Rollenhagen
Institute for Neuroscience and Medicine INM-2, Research Centre J€
ulich, J€
ulich, Germany
e-mail: a.rollenhagen@fz-juelich.de
J.H.R. L€ ubke (*)
Institute for Neuroscience and Medicine INM-2, Research Centre J€
ulich, J€
ulich, Germany
Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH/University Hospital Aachen
and JARA Translational Brain Medicine, Aachen, Germany
e-mail: j.luebke@fz-juelich.de
# Springer Science+Business Media New York 2016 225

D.W. Pfaff, N.D. Volkow (eds.), Neuroscience in the 21st Century,
DOI 10.1007/978-1-4939-3474-4_11
226 A. Rollenhagen and J.H.R. L€
ubke
integrate and process thousands of excitatory, and to a lesser extent inhibitory,

synaptic inputs terminating either on the dendritic shaft or spine. The morphology
and size of dendrites critically determines the mode of connectivity between
neurons with dendritic trees ramifying in characteristic spatial domains where
they receive specific synaptic inputs. Therefore, dendrites play a critical role in
the integration of these inputs and in determining the extent of action potential
generation.
Furthermore, the structure and branching of dendrites together with the avail-
ability and variation in voltage-gated ion conductances strongly influences how
synaptic inputs within a given microcircuit are integrated. This integration is both
temporal – involving the summation of signals as well as spatial – entailing the
aggregation of excitatory and inhibitory inputs from individual branches. Den-
drites were thought to convey electrical signals passively. However, as shown
recently dendrites can activly support action potentials and release neurotrans-
mitters, a property that was originally believed to be specific to axons.
Voltage changes at the soma result from activation of distal synapses propa-
gating to the soma without the aid of voltage-gated ion channels. Based on the
passive cable theory one can measure how changes in dendritic morphology lead
to changes of the membrane voltage, and thus how variation in dendrite archi-
tectures affects the overall output characteristics of the neuron. In this context it is
also important to know that the membrane of dendrites contain ensembles of
various proteins that may contribute to amplify or attenuate synaptic inputs.
Sodium, calcium, and potassium channels are all implicated to affect input
modulation. Each of these ions has a family of channel types with its own
biophysical characteristics relevant to synaptic input modulation thereby control-
ling the latency of channel opening, the electrical conductance of the ion pore, the
activation voltage and duration. This could lead to an amplification of even weak
inputs from distal synapses by sodium and calcium currents. One important
feature of dendrites, endowed by their active voltage gated conductances, is
their ability to propagate action potentials back into the dendritic tree. Known
as “backpropagating action potentials,” these signals depolarize the dendritic tree,
a mechanism that contributes to synaptic modulation and long- and short-term
potentiation and plasticity.
Abnormalities in dendritic structural plasticity are a characteristic feature of
many mental, neurological and neurodegenerative brain disorders. Changes in
synaptic function or neuronal circuitry associated with disease produce severe
structural changes in dendritic length and branching, dramatic loss of spines
accompanied also by changes in spine morphology. Thus, pathologies in dendritic
structure are followed by remodeling of dendritic and synaptic circuits and
changes in learning, memory and mind of the brain.
Keywords
Activity-dependent synaptic plasticity • Arborization pattern, dendrites • Asso-
ciativity • Asymmetric synapses • Backpropagating action potentials • Behavioral
experiments • Cooperativity • Dendrites • Estradiol • Excitatory postsynaptic
10 Dendritic Elaboration: Morphology and Chemistry 227
potentials (EPSPs) • Filopodia • Hormone induced structural dendritic plasticity •

Long-term potentiation (LTP) • NMDA receptor • Racemose appendages • Sessile
spines • Smooth endoplasmatic reticulum-cysternae • Spike-timing-dependent
plasticity (STDP) • Structural induced plasticity • Synapse specificity • Synaptic
bouton • Varicosities in dendrites
Structure of Dendrites
The remarkable structure of dendrites was already described in great detail by Golgi
and Ramón y Cajal nearly 100 years ago and since then in numerous, uncountable
publications and Cajal’s famous textbook “Histology of the Nervous System”
(English translation: Ramón y Cajal 1995; summarized by Fiala et al. 2008; Stuart
et al. 2008). In contrast to Golgi, one of the strong advocates of the syncytium theory
Ramón y Cajal from the beginning demonstrated that neurons exhibit two types of
processes, dendrites and axons that do not interconnect in anastomotic continuity.
This finally leads to the establishment of the neuron doctrine that neurons are
independent entities, the smallest structural and functional building blocks (units)
of the nervous system. Dendrites are regarded as the input structure where neurons
receive electrical signals from axons of other neurons and conduct these signals via
the cell body to its own axon as the output structure. Therefore dendrites represent
the receptive surface of a given neuron. Dendrites of different neuronal cell types
exhibit enormously diverse forms with respect to shape, total dendritic length
(60–52,000 μm), branching (unbranched to 500 branchpoints), diameter (proximal
dendrites: from 1 to 8 μm, distal dendrites: from 0.2 to 3 μm), and polarity
(Fig. 1a–o). Thus larger neurons typically have both larger cell bodies and more
extensive dendritic fields.
The variability of the dendritic tree can reach from short, nearly unbranched
configurations (Fig. 1e) to highly complex dendritic trees (Fig. 1f, n, o). Although
dendrites are regarded as local structures when compared with the axon, individual
dendrites can reach out for more than 500 μm, e.g., in giant Betz pyramidal neurons
in the motor cortex. The complexity of the dendritic tree critically determines the
mode of connectivity through the number of input synapses established by the axons
of other neurons. Many dendrites are organized in characteristic spatial domains
(Fig. 1c, j, k, n, o) where they receive specific synaptic inputs. Therefore, dendrites
play a critical role in the integration of these inputs and in determining the extent of
action potential generation. Neurons exhibiting more simple dendritic trees
(Fig. 1e, h) have a very limited surface area (receptive field) for receiving inputs.
By extending their dendrites (Fig. 1a–c, f, o) neurons can increase their surface
area enormously without excessively increasing their volume. For example, 80 %
of the surface area of dendrites of excitatory neurons are covered with spines
(Peters and Kaiserman-Abramof 1970; Feldman 1984; Larkman 1991; reviewed
by DeFelipe and Farinas 1992; summarized by Ramón y Cajal 1995) the major
input source for a neuron, suggesting that an increase of surface area is indeed
critical for the number of synaptic inputs to a neuron.
ubke
a b h i j
c d
e m
g
f
k
n o
L1
L2/3
L4
L5A
L5B
L6
100 µm
Fig. 1 Variability of dendrites in various regions of the vertebrate and invertebrate nervous
system. (a) neuron in the cat motor cortex; (b) interneuron within the locust nervous system; (c)
thick tufted pyramidal cell in the rat neocortex; (d) cat retinal ganglion cell; (e) amacrine cell in the
salamander retina; (f) Purkinje cell in the human cerebellum; (g) neuron in the rat thalamus; (h)
granule cell in the mouse olfactory bulb; (i) spiny projection neuron in the rat striatum; (j) neuron in
the nucleus of Burdach in humans; (k) Purkinje cell in the cerebellum of a mormyrid fish; (l) Golgi-
like glial cell in the mouse cerebellum. (m) axonal arborization and dendrites of an isthmotectal
neuron in the turtle. All dendritic arborizations and axons are given in black, the somata in red. (n)
Pyramidal neurons in different cortical layers throughout the rat somatosensory neocortex with their
apical dendrites forming dendron-like structures. Pyramidal cells are the main building block of the
cortical column. (o) Pyramidal cells in the CA1 subregion of the mouse hippocampus showing a
Finally, phylogenetic differences in specific neuronal morphologies further sup-

port a direct relationship of dendritic complexity and the number of connections
established on a given neuron. The complexity of many neuronal cell types in
vertebrates and invertebrates (cerebellar Purkinje cells, cortical and hippocampal
pyramidal cells, several types of GABAergic interneurons) increases with the phy-
logenetic evolution of the brain driven by the need to establish more connections
with specific cell types at specific locations.
Dendritic Arborization Patterns
The morphology of the dendritic tree has been and is still used to classify neurons.
However, classification of morphologies is difficult because of the number of
different dendritic branching patterns between the various neuronal cell types
and even within a given cell class. Often simple schemes were used to classify
neurons as being adendritic with no dendrites (dorsal root and sympathetic gan-
glion cell), unipolar, (cerebellar Purkinje cell, olfactory granule cell, see also
Fig. 1b, f, h, k, l) bipolar or spindle (bipolar cell of the retina and bipolar
interneurons of the neocortex, see also Fig. 1j), and multipolar (retinal ganglion
cells, spiny stellate neurons in layer 4 of the neocortex, see also Fig. 1a, d, g, i)
based on the number and orientation of the dendritic tree. A further, more detailed
classification has been developed to classify the huge variety of multipolar neu-
rons. A common dendritic arborization pattern is the spherical or stellate radiation
where dendrites emerge and radiate in all directions from the cell body. Typical
examples are spinal neurons, neurons in the inferior olive, pons, thalamus, and
striatum. Furthermore, the multipolar dendritic arborization could be limited to a
given layer or domain (planar laminar radiation [retinal horizontal cells]) or display
an offset laminar radiation (retinal ganglion cells) or a multilaminar radiation
(retinal amacrine cells). In addition, dendritic arborization patterns were described
by cylindrical, conical, biconical, and by fan radiation (summarized by Fiala
et al. 2008). Many quantitative methods have been used to measure the length
(Sholl analysis, originally introduced by Sholl 1956) and density of the dendritic
tree. Branch order can be analyzed with the centrifugal method or more specifically
with the fractal dimension method that allows quantifying the degree to which the
dendritic tree fills its special domain.
Fig. 1 (continued) dense plexus of their basal dendrites in the stratum radiatum and bundles of their
apical dendrites in the stratum oriens. The picture is taken from a 300 μm thick living brain slice
from a mouse strongly expressing yellow fluorescent protein (YFP-H line; Jackson Laboratories).
(a–m) (With permission from the Massachusetts Institute of Technology, adopted and modified
from Mel BW (1994) Neural Computation 6: 1031–1085). (n) (Reprinted with permission from
NeuGen, based on Eberhard et al. 2006; Wolf 2011; Wolf in process). (o) (Adopted from www.
zeiss.de/./bbe5e37ac0c877d3c12570eb004c1127)
ubke
Subcellular Structure of Dendrites
Electron microscopy is the only way to describe the intracellular (internal) structure
of dendrites in great detail (Fig. 2). Since dendrites emerge from the cell body,
proximal dendritic segments show a similar organization and content of organelles
like cell bodies such as the Golgi apparatus and rough (granular) endoplasmic
reticulum supporting the view that dendrites are extensions of the cell body. The
cytoskeleton of dendrites is composed of microtubules, neuro- and actinfilaments
(Fig. 2a–c). Microtubules belong to the transport machinery of dendrites and play an
important role in the transport of mitochondria and other organelles (Overly
et al. 1996). Microtubules are thin elongated structures oriented to the longitudinal
axis of the dendrite and form regular arrays along the extent of the dendrite (Fig. 2c).
It was shown that the number of microtubules is proportional to the diameter of the
dendrite (Fiala et al. 2003). Microtubules are present also in axons with a high
accumulation in the axon initial segment.
Fine astrocytic processes lack microtubules and are therefore distinguishable
from dendrites with small calibers (Fig. 2c). Smooth endoplasmatic reticulum
(SER; Fig. 2b, f) can be found throughout the entire extension of dendrites and is
thought to maintain and regulate cytoplasmic calcium levels. The SER sometimes
aggregates into large vacuoles; the so-called SER-cysternae (Fig. 2b), that forms a
continuous reticulum throughout the dendrites (Harris and Stevens 1988; Spacek and
Harris 1997; Cooney et al. 2002; summarized by Fiala et al. 2008). Several other
organelles such as coated pits and vesicles involved in the endocytosis process are
frequently found at the membrane of dendrites. Recycling and sorting endosomes
form tubular compartments and are not part of the endoplasmatic reticulum. Sorting
endosomes mature into multivesicular bodies (Fig. 2d). Another characteristic ele-
ment of dendrites are mitochondria (Fig. 2a–f). They are often oriented parallel to the
microtubular system and can form large networks. In large neurons like pyramidal
neurons in the hippocampus and neocortex mitochondria occupy about 2–5 % of the
overall surface of the dendrite. It has been shown that dendrites with a high density
of synaptic inputs show a higher density of mitochondria (Peters et al. 1991; sum-
marized by Fiala et al. 2008).
Dendritic Specializations and Appendages
The capacity of the brain in the processing and storage of information critically
depends on the number of different neurons in a given neuronal network that can
potentially be synaptically connected (Chklovskii et al. 2004). The mode of con-
nectivity depends primarily on the pattern of dendritic and axonal arborizations and
secondarily by the formation of the various forms of dendritic appendages. Den-
drites, in particular those of excitatory neurons exhibit dendritic specializations
which range from varicosities to various forms of dendritic spines (Fig. 3). Dendritic
spines increase not only the surface area of a neuron by up to 30 %, but also increase
the number of potential synaptic partners of an individual neuron by extending the
a b
mi
tt mi
tt * ***
*mt
tt tt
ad c rib
nf
mi mt de1
ad
mt
* syn1
de2
syn2
e
*
d
de
syn
*
sp syn
sa
* f
som
er
mvb
de
Fig. 2 Electron micrographs showing various subcellular organelles of dendrites. (a) Apical
dendrites (ad) of pyramidal cells with their characteristic branching into terminal tufts (tt) in the
rat visual cortex. The cytoplasm of the dendrites contains numerous mitochondria (mi) of different
shape and size and a dense system of microtubules (mt). (b) Cross section through a secondary
ubke
reach of dendrites for a pool of axons (Chklovskii et al. 2004). Spine densities could
differ substantially between neurons and individual dendritic segments or branches
reflecting the differences in connectivity of different excitatory inputs. The density
and distribution pattern of spines and spine-like appendages along the dendritic tree
establish different innervation domains for input synapses that dramatically influ-
ence the processing and storage of incoming signals and as a consequence drive
synaptic transmission and short- and long-term plasticity.
Dendritic spines are highly specialized, independent biochemical and functional
compartments of dendrites. These membrane specializations are the postsynaptic
elements of synaptic complexes. The following dendritic specializations and
appendages can be found throughout the nervous system.
Varicosities (Fig. 3a) in dendrites are mainly found in amacrine cells of the retina.
They are thin with numerous swellings and contact rod bipolar cells (Ellias and
Stevens 1980). These varicosities receive synapses from rod bipolar cells and in turn
establish synapses with these neurons. Dendritic varicosities are also frequently
found on several types of GABAergic interneurons but their function is still less
clear.
A second type of dendritic specializations are filopodia that are characterized by a
long thin abruptly ending protrusion sometimes with a small swelling at the tip
(Fig. 3b, b1). They are highly dynamic and could extent and retract within minutes
(Dailey and Smith 1996; Fischer et al. 1998; Engert and Bonhoeffer 1999). Filopodia
are transient dendritic structures and are thought to play a role in synaptogenesis
often establishing nascent synaptic contacts (Fiala et al. 1998) although many
filopodia never establish synaptic contacts. There is growing evidence that filopodia
may develop into mature spines. Filopodia are rarely seen in adult brains only under
pathophysiological conditions and are generally replaced by shaft synapses or other
types of membrane specializations.
Dendritic spines are the most common membrane specializations on dendrites
and display enormously diverse forms. Simple spines, the major class of dendritic
Fig. 2 (continued) dendrite of a Purkinje cell in the rat cerebellum. Microtubules (mt) are
intermingled within the agranular reticulum some of which are highlighted by asterisks in the red
box. Several mitochondria (mi) are found at the edges. (c) Longitudinal (de1) and transverse (de2)
section through dendrites in the rat spinal cord. In de1 individual microtubules (mt), neurofilaments
(nf), and a cluster of ribosomes (rib) can be seen throughout the cytoplasm. The second dendrite
(de2) receives two axon terminals (syn1, syn2) synapsing directly on its shaft. Both the dendrite and
the axon terminals are ensheated by astrocytic processes as indicated by the asterisks. (d) High
magnification of a pyramidal cell dendrite (de) in the rat neocortex with a spine (sp) receiving an
asymmetric (excitatory, marked by red asterisks) synapse containing a large pool of synaptic
vesicles. Note the presence of a prominent spine apparatus (sa) and multivesicular body (mvb)
within the cytoplasm. (e) Dendro-dendritic synapse between a mitral and granule cell in the
olfactory bulb ( framed box). (f) Two somato-dendritic synapses ( framed boxes) between granule
cell dendrites and the soma of a mitral cell as indicated by the rough endoplasmatic reticulum (er)
(With permission from Oxford University Press taken from Peters, Palay and Webster “The fine
structure of the nervous system: neurons and their supporting cells.” (3rd eds.))
Fig. 3 Dendritic specializations. (a) Schematic drawing of a dendritic varicosity as exemplified for
a thin dendrite of a retinal amacrine cell. (b) Dendritic filopodium with a long thin protrusion
terminating abruptly without a bulbous ending; b1, Photomicrograph of a growing dendrite with
numerous filopodia along its course (With permission from Portera-Cailliau Laboratory, UCLA,
Reed Neurological Research, Ctr-A-145, 710 Westwood Plaza, Los Angeles CA, USA, Copyright
# 2008 90095). (c) Schematic drawings of a simple sessile, stubby, and crook thorn spine as
typically found on neocortical pyramidal cells and neurons of the cerebellar dentate nucleus. (d)
Schematic drawings of a pedunculated thin, mushroom, and gemmule spine in the cerebral cortex
and olfactory bulb; d1, Fluorescent picture of a dendrite with numerous spines of different shape
and size including the spine types described above (With permission of MIT Press, 55 Hayward
ubke
specializations are either sessile (Fig. 3c) or pedunculated (Fig. 3d, d1). Sessile
spines (stubby spines; Peters and Kaiserman-Abramof 1970) are appendages without
a prominent spine neck and no bulbous swelling at the end (Fig. 3c). Pedunculated
spines are characterized by a thin stalk or neck of various lengths (0.1–1 μm) and a
bulb-like terminal ending that could vary substantially in both shape and size
(0.02–0.7 μm2). They could be classified as thin, mushroom, and gemmule spines
(Fig. 3d). At a given dendrite all types of spines could be found side by side
(Fig. 3d1). Simple spines are found throughout the nervous system including
cerebral pyramidal cells, granule cells of the dentate gyrus and cerebellar Purkinje
cells. However, the occurrence, density, and distribution of the different spine types
vary substantially between different neuronal cell types and even within a certain
neuronal cell class. Simple spines, exclusively from the sessile type, are also found
on several classes of GABAergic interneurons, namely on sparsely or non-spiny
(smooth) interneurons (for example Gupta et al. 2000; Helmstaedter et al. 2009a;
reviewed by Freund and Buzsáki 1996; Somogyi and Klausberger 2005). An
extended form of a simple spine is the so-called branched spine that shares a
common stalk where each branch receives an individual synaptic contact (Fig. 3e,
e1). These spines were infrequently found on spiny, in particular pyramidal neurons,
namely in the hippocampus and neocortex (Larkman and Mason 1990; Mason and
Larkman 1990; Harris et al. 1992; Trommald and Hulleberg 1997). Interestingly,
they are more common on neurons with a larger number of branches like cerebellar
Purkinje neurons (Harris and Stevens 1988).
So-called thorny excrescences are highly specialized pedunculated spines that
form a densely lobed dendritic protrusion forming a glomerulus-like endbulb
(Fig. 3f, f1) associated with large axonal terminals like the hippocampal (Hamlyn
1962; Chicurel and Harris 1992; Rollenhagen et al. 2007) and cerebellar mossy fiber
bouton (Xu-Friedman et al. 2001; Xu-Friedman and Regehr 2003). The number and
complexity of these thorny excrescences varies substantially between different spiny
Fig. 3 (continued) Street, Cambrigde, MA 02141, USA taken from Yuste, Rafael: Dendritic spines
ISBN 978-0-262-01350-5). (e) Branched spines where each branch has a unique presynaptic partner
as shown for CA1, CA3 pyramidal cells, granule cells of the dentate gyrus, and cerebellar Purkinje
cells; e1, 3-D reconstruction of a complex branched spine (blue) of a CA3 pyramidal neuron, three
active zones, transmitter release sites, are highlighted in red (With permission from the Journal of
Neuroscience taken from Rollenhagen et al. (2007)). (f) Thorny excrescences with densely lobed
dendritic protrusions typical for CA3 pyramidal cells and dentate gyrus mossy cells; f1, Fluorescent
image of a proximal dendritic segment with three prominent thorny excrescences (white asterisks)
(With permission from en.domotica.net/Apical_dendrite). (g) Racemose appendages are twig-like
branched dendritic segments with synaptic varicosities terminating in a bulb-like ending typical for
inferior olive and lateral geniculate nucleus neurons. (h) Coralline excrescence with dendritic
varicosities extending into numerous thin protrusions characteristic for dendrites of neurons in
the dentate and lateral vestibular nucleus (Schematic drawings are adopted and modified from
Table 1.3 in Dendritic Structure Chap. 1 by Fiala, Spacek, and Harris edited in Dendrites (2nd eds.)
by Stuart et al. 2008)
neurons, even on the same or different dendrites of a given neuron, with some having
many or only a few lobes (Fig. 3f, f1).
Racemose appendages (Fig. 3g) have a more sparsely lobed appearance. They are
twig-like branched dendritic appendages containing synaptic varicosities and bul-
bous tips and are most common on neurons in the inferior olive (Ruigrok et al. 1990),
but can be also found on several classes of spiny neurons e.g., neocortical spiny
stellate and pyramidal neurons.
Coralline excrescences are highly complex varicosities with numerous synaptic
protrusions with sometimes thin tendrils similar to filopodia (Fig. 3h). The appear-
ance of these filopodia on dendrites of adult neurons of the cerebellar and vestib-
ular nuclei suggests that these excrescences represent growth processes of
dendrites.
In summary, individual neurons throughout different brain regions exhibit a
variety of spine types and other dendritic appendages (summarized by Fiala
et al. 2008). All dendritic specializations are highly dynamic structures that could
undergo dramatic changes throughout life (reviewed by Nimchinsky et al. 2002;
Yuste et al. 2000; Yuste 2010) which makes a morphological classification difficult
since these specializations may evolve into different forms, e.g. from filopodia to
mature spines over time (Prieto and Winer 1999). It may be speculated that geometry
and size of spines and spine-like appendages is determined by the microcircuit in
which the neurons are embedded and by local connectivity.
Fine Structure of Dendritic Spines
The large variability of spine geometries is accompanied also by a huge diversity in

their intracellular composition. It should be noted that some subelements such as
mitochondria are only found in larger spines, e.g., filopodia and simple spines rarely
contain mitochondria whereas for example varicosities and thorny excrescences
could contain a few or many mitochondria. Some spines also contain the dendritic
SER-network, however, their density and distribution varies substantially between
neurons of different cell classes (Fig. 2d). In the cerebral cortex and the hippocampus
large spines processing perforated synapses contain a special form of SER with a
flattened and laminated appearance, the so-called spine apparatus (Gray 1959;
Spacek 1985; reviewed by Segal et al. 2010, see also Fig. 2d). Spine apparati are
frequently found on mushroom spines, gemmules and thorny excrescences (Fig. 4b).
Smooth and coated vesicles and polyribosomes are also found in spines. However,
their density and distribution depends on different levels of the metabolic and
neuronal activity. At resting conditions only a small fraction of spines contain
polyribosomes, intense activation increases the number of polyribosomes dramati-
cally (Ostroff et al. 2002). This increase in polyribosomes in perforated, also spine
apparatus containing large spines and excrescences may represent high metabolic
activity engached in synaptic plasticity and the formation of short-term memory
(Steward and Reeves 1988). The cytoskeleton of simple spines and filopodia is
composed of actin rather than microtubules. Actin-based cytoskeletons are thought
ubke
to facilitate rapid calcium-induced changes in their shape (Fifková 1985a, b; Fischer

et al. 1998; Halpain et al. 1998, see also Fig. 6b, c).
Spines represent the postsynaptic elements of the synaptic complex composed
of the bulbous dendritic swelling and the endbulb of an axon, the so-called synaptic
bouton (Fig. 2d). In general, two types of synapses based on the shape and size of
synaptic vesicles and the appearance of the pre- and postsynaptic density either
being symmetric or asymmetric (Gray 1959; Colonnier 1968; for review see
DeFelipe and Farinas 1992) exist. Asymmetric synapses are regarded to be excit-
atory using either glutamate or aspartate as their neurotransmitter. Simple and
pedunculated spines usually contain only a single often large macula and some-
times a perforated active zone (transmitter release site; Rollenhagen et al. 2007;
Fig. 2d). Simple spines occasionally receive a second synapse either located at the
endbulb or the spine neck. Complex spines like thorny excrescences on CA3
pyramidal cells could have as many as eight active zones (Rollenhagen
et al. 2007). The pre- and postsynaptic densities of complex spines show ring-,
patch-, or band-like forms often with a perforated appearance. The majority of
asymmetric synapses (~80 %) terminate on dendritic spines, the remaining are
found directly on the dendritic shaft. Dendritic spines occasionally have small
protrusions extending into the presynaptic bouton called spinules. These spinules
are surrounded by invaginations of apposed membranes, could originate from all
parts of the dendritic surface and were found at synaptic complexes in different
brain regions. Beside synaptic complexes established by a dendrite or spine with a
synaptic bouton, so-called dendro-dendritic (Fig. 2e) and dendro-somatic com-
plexes (Fig. 2f) have been described as highly specialized, but rare signal trans-
duction elements.
Finally, synaptic complexes established on spines are surrounded by glia. In
particular, astrocytes and their fine processes, play an important role in synaptic
function, acting as physical barriers to glutamate diffusion and mediating transmitter
uptake by glutamate transporters (reviewed by Danbolt 2001). For example, in the
neocortex and hippocampus synaptic complexes are isolated from the surrounding
neuropil and other synaptic complexes by a dense network of fine astrocytic
processes (Fig. 2c). In contrast to other synapses, glial fingers were never observed
to reach as far as the individual active zone at the CA3 – mossy fiber synapse. At
neocortical synapses glial processes were regularly found at the pre- and postsyn-
aptic apposition zone at the synaptic cleft (Ventura and Harris 1999; Rollenhagen
et al., unpublished observations). At certain dendritic spines only a partial or no
ensheathment by glia has been observed. The presence and absence of glia deter-
mines the rate of glutamate spillover and as a consequence synaptic cross talk at a
given synaptic complex (Bergles et al. 1997).
Taken together, the pattern of the dendritic arborization is directly linked to the
connectivity of neurons. The enormous diversity in dendritic structure, composition,
and plasticity together with the diversity of dendritic spines as targets for excitatory
synaptic inputs suggests an also divers functional contribution of dendrites to
learning, memory and mind of the brain.
Functional Plasticity
Dendritic Plasticity
It has been long thought that dendrites are passive structures that only receive
signals. It is now well established that dendrites are more complex than originally
thought. Beside their classical role as receiving structures for synaptic inputs they
also act as transmitters and integrators and convey information about local activity
across a small number of synapses. The majority of synapses are established on
dendrites, and most excitatory connections are made on spines. Synaptic plasticity is
thus an intrinsically function of dendrites and spines. Activity-dependent synaptic
plasticity is a fundamental characteristic for many brain functions, including refine-
ment of dendritic structure, learning and memory, and other higher cognitive brain
functions (reviewed by Martinez and Derrick 1996; Stevens 1998).
The aim of this chapter is to summarize experimental data and theoretical
considerations relevant to the role of dendrites and spines in synaptic plasticity
with a focus on associative Hebbian synaptic plasticity including long-term poten-
tiation and spike-time dependent forms, mediated by NMDA-receptor activation.
However, since a variety of different pre- and postsynaptic factors (signal cascades)
modulate synaptic plasticity we will focus primarily on those factors related to the
postsynaptic element, dendrites and spines (for the role of presynaptic factors see
DENDRITES edited by Stuart et al. 2008, Chap. 18).
It was postulated by Donald Hebb (1949) that “when the axon of neuron A is
close enough to excite neuron B or repeatedly or persistently take part in firing it,
some growth process or metabolic change has to take place in both the pre- and
postsynaptic neuron such that the efficacy of neuron A, as one of the neurons
firing B, is increased.” It is now established that the discovery of the NMDA receptor
dependent long-term potentiation (LTP) is the fundamental mechanism how neu-
rons, dendrites, and synapses implement Hebbian plasticity. Beside synaptic poten-
tiation a mechanism for depression exists to complement potentiation. Two forms of
synaptic depression are known: homosynaptic long-term depression (LTD) found at
hippocampal and neocortical synapses (reviewed by Bear and Malenka 1994), and
associative LTD at the cerebellar Purkinje cell synapse.
Long-Term Potentiation
The NMDA receptor is sensitive to neurotransmitter release and membrane depo-

larization and can therefore detect the conjunction of pre- and postsynaptic neuronal
activity. LTP is a special form of synaptic strengthening (reviewed by Bliss and
Collingridge 1993, see also Fig. 4). LTP was originally described between neurons
in the entorhinal cortex and dentate gyrus of the hippocampus (Bliss and Lomø
1973). Activation of this pathway by a brief, high-frequency train of stimuli let to a
rapid and sustained long-lasting increase in synaptic strength. Similar forms of this
ubke
a c1
a
s lve
str tr. o us
. p rie
yra ns
EPSP potentiation S1 (%)

mid
str
. ra
ali
s 2mV
dia
tum
50
str 10ms
. la
cu
no
su
str m
.m
ole
str cu
lar
0
.g e
ran
ulo
hilus su
m
D D
–50
0 1 2
b c2
100
5mV
EPSP potentiation S2 (%)

10ms
EPSP potentiation (%)
100 50
50
0
0
–50 –50
0 1 2 3 4 0 1 2
Time (hrs)
Fig. 4 Basic features of LTP in the hippocampus. (a) Schematic diagram of the hippocampus
showing the principal subregions CA1, CA3 pyramidal cell layers, granule cell layer of the dentate
gyrus (DG), and the main excitatory pathways (perforant path, mossy fibers, Schaffer collaterals,
and commissural fibers). (b) In vivo field potential recordings in the somatic region of the dentate
gyrus following stimulation of the perforant path recorded before (upper left trace) and 3 h (upper
right trace) after LTP induction (marked by the black triangle), using a 250 Hz, 200 ms tetanus.
Note the significant increase of the in slope of the population EPSP (red dots, lower diagram). (c)
c2, Demonstration of cooperativity, associativity, and synapse-specificity of LTP. Recording
arrangement: two extracellular recording electrodes were placed on both sites of the recording
area, the dendritic field of CA1, to activate two independent inputs (S1 and S2). S1 represents a
weak input and S2 a stronger one. The left trace represents the population EPSP for the weak, the
right trace for the strong stimulus. Tetanic stimulus of S1 (first open triangle) produced no long-
lasting increase in synaptic efficacy since the synaptic drive was below the cooperativity threshold
for LTP (c1). A tetanus to S2 (first black triangle) produced a robust LTP in this pathway but no
change in S1 also demonstrating synapse specificity. Simultaneous tetanic stimulation of both
pathways (second open and black triangles) produces associative LTP in the weak pathway S1
(c2) (b, c with permission from Oxford University Press taken from Bliss and Collingridge (1993))
long-lasting activity-dependent synaptic enhancement was found in many brain

regions such as hippocampus, neocortex, striatum, and other central as well as
peripheral synapses (reviewed by Bear and Kirkwood 1993). The most studied
synapse in LTP is that of the Schaffer collateral axons from hippocampal CA3 to
CA1 neurons (Fig. 4a). Excitatory spiny neurons, in particular pyramidal cells, in
various brain regions show pronounced LTP. However, despite mechanistic similar-
ities LTP could differ substantially at different synaptic connections as demonstrated
for the mossy fiber – CA3 pyramidal cell synapse (Salin et al. 1996; reviewed by
Nicoll and Schmitz 2005) when compared with CA1 LTP (Nicoll and Malenka 1995;
reviewed by Johnston et al. 1992) or mossy fiber – GABAergic interneuron synapses
(Tóth et al. 2000). To understand the underlying mechanisms of LTP the role of the
NMDA receptor, one of the main contributors, is briefly summarized in this context.
Properties of the NMDA Receptor

One of the requirements of a Hebbian synaptic modification is coincidence detection
of both pre- and postsynaptic activity. The NMDA receptor is thought to be the
Hebbian detector underlying LTP, although NMDA receptor-independent forms of
LTP have also been described (Nicoll and Malenka 1995). One important character-
istic of the NMDA receptor is that it only opens when both the pre- and postsynaptic
neurons are activated. In addition, a presynaptic chemical signal via a neurotrans-
mitter and a postsynaptic electrical signal in form of a local membrane depolariza-
tion are required. As a result calcium ions enter the postsynaptic neuron thereby
activating calcium sensible enzymes that either lead to frequency-dependent synap-
tic potentiation or depression. In dendrites or spines two major excitatory neuro-
transmitter receptors, namely the AMPA- and NMDA receptors and their subunits,
were found (named for their artificial agonists, α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionate and N-methyl-d-aspatarte). The AMPA receptor provides the
primary depolarization and synaptic activation while the NMDA receptor is viewed
as a secondary source of depolarization, thereby driving synaptic plasticity. The
sensitivity of the NMDA receptor to glutamate is high and more sensitive to lower
concentrations than that of the AMPA receptor. This high affinity is also associated
with a slow deactivation (temperature-dependent decay time constant) and is there-
fore a long-lasting indicator of synaptic activity. A crucial characteristic of the
NMDA receptor is its only opening by a strong depolarization of the membrane.
Binding of glutamate results in the opening of the pore, but conduction of the
channel is blocked by extracellular Mg2+. Depolarization expels Mg2+ allowing
the influx of a mixture of Na+, K+, and Ca2+ dependent membrane potential
(Nowak et al. 1984). It was shown that the kinetics of the Mg2+ have fast and slow
components (Spruston et al. 1995a; Kampa et al. 2004). It has to be noted that the
NMDA receptor is also sensitive to other molecules including glycine, zinc, poly-
amines, histamine, redox agents, various steroids, calmodulin, kinases and phospha-
tases etc. (reviewed by McBain and Mayer 1994; Nicoll and Schmitz 2005).
NMDA receptors also display a high degree in molecular diversity. Beside the
most abundant NR1 subunit, other subunits such as NR2A-D have been described,
some of which are also developmentally regulated (reviewed by Lujan et al. 2005)
The composition of these subunits together with the existence of various splice
variances (reviewed by Zukin and Bennett 1995) confer the huge differences in the
functional properties of these receptors (Baude et al. 1995; Kharazia and Weinberg
1999; Takumi et al. 1999; reviewed by Nusser 2000) across different neuronal cell
types. Of particular interest are subunit-specific differences in deactivation and Mg2+
sensitivity. Neurons with different subunit compositions display shorter or longer
integration times or sensitivity to postsynaptic depolarization. Diversity within a
ubke
single neuron may also be important depending on the class of presynaptic afferents
(Maccaferri et al. 1998). Finally, a crucial property of the NMDA receptor in
regulating synaptic plasticity is its Ca2+ permeability (MacDermott et al. 1986;
Ascher and Nowak 1988; summarized by Mainen and Abott 2008).
Dendritic Integration and Its Role in Synaptic Plasticity

For the integration and modulation of synaptic plasticity at dendrites three require-
ments seems to be fundamental for LTP induction: cooperativity, associativity and
spine-synapse specificity (Fig. 4b, c). Cooperativity is the requirement for the nearly
simultaneous activation of a threshold level of synaptic inputs or practically speak-
ing to the sensitivity either to the stimulus frequency during the tetanus or the
intensity of the extracellular stimulation of presynaptic axons. Interestingly, LTP
induction seems to be independent from the number of inputs activated or stimulus
intensity, depolarisation combined with low-frequency stimulation is sufficient to
induce and drive LTP (Bliss and Lomø 1973; Colino et al. 1992, see also Fig. 4b). In
turn, hyperpolarization or inhibition is sufficient to prevent LTP (Kelso et al. 1986;
Malinow and Miller 1986). Dendrites mediate both the spatial and temporal integra-
tion of depolarization of activated synapses thereby shaping the cooperativity of LTP
induction with the simplest form that dendrites just sum up their synaptic inputs.
However, the initiation and active propagation of action potential in the dendritic tree
is an important contribution to the depolarization seen by the synapses and
strengthens cooperativity (Fig. 4c2). Computer simulations have shown that
cooperativity is increased among clustered arrangements of synaptic inputs when
compared with diffuse synapse distribution (Mel 1993) which lead to a strengthening
of synaptic activity which is correlated and dendritically clustered (Polsky
et al. 2004; reviewed by Mehta 2004).
Associativity refers to the ability of a “test” pathway to be potentiated when
simultaneously activated with a “conditioning” pathway (Fig. 4c1, 2). The test
pathway is only weakly stimulated with no induction of LTP whereas the condition-
ing pathway undergoes strong stimulation providing enough depolarization to
induce LTP. Associativity describes the phenomenon that the strong pathway pro-
vides sufficient depolarization to drive LTP induction of the weak pathway by
co-activation (Fig. 4c2). Therefore, associativity refers to cooperation of different
sets of synapses. Associativity of LTP was first described in vivo in the dentate gyrus
by pairing weak inputs from contralateral entorhinal cortex with strong ipsilateral
inputs (McNaughton et al. 1978; Levy and Steward 1983) and was also demon-
strated later in slice preparations of the CA1 region (Barrionuevo and Brown 1983).
As with cooperativity, electrical dendritic integration mediates the associativity of
synapses. It should be noted that the spatial relationship and the different synaptic
weight in the two pathways could influence and modify the mode of associativity.
It has been demonstrated that inhibition may critically regulate the induction of
dendritic synaptic plasticity. Blockade of inhibition considerably changes the stim-
ulus conditions required for LTP induction raising the probability to induce LTP. For
example, primed or theta bursts effectively induce LTP by effective disinhibition
(Pacelli et al. 1989) through presynaptic GABAB autoreceptors on GABAergic
terminals (Davies and Collingridge 1996). Inhibition also severely alters the inte-
grative properties of dendrites (Häusser and Clark 1997; Pare et al. 1998). Inhibition
interacts with excitation by summation (hyperpolarizing the membrane) or multipli-
cation (shunting inhibition) thereby lowering the voltage levels reached postsynap-
tically or even preventing the initiation of action potentials. However, the mode of
inhibition is dependent on the precise location of inhibitory synapses and their
temporal relationship of their activation to active excitatory synapses (Raastad
et al. 1998).
Spike-Timing-Dependent Plasticity
Spike-timing-dependent plasticity (STDP) is a special type of synaptic potentiation

and is thought to allow the memorization and learning of temporal signal integration
in the dendritic tree. STDP has been shown for neurons in various brain regions
(reviewed by Abbott and Nelson 2000) including neocortex (Markram et al. 1997;
Feldman 2000) and hippocampus (Debanne et al. 1994, 1998). If normal STDP,
synapses are strengthened by repetitive pairing of spikes in the pre-before-post order
and are weakened by pairing in the reverse order. Therefore, taken the properties of
the NMDA receptor into account (see above) one would predict that the temporal
order of the pre- and postsynaptic signals to be critical. The presynaptic signal must
precede the postsynaptic one by a time window less than the decay of the NMDA
glutamate binding to achieve unblocking, the reverse order would not be effective.
More recent studies pairing postsynaptic action potentials with excitatory postsyn-
aptic potentials (EPSPs) showed a critical temporal coincidence (asymmetrical time
window) of the two signals (Markram et al. 1997; Debanne et al. 1998; Feldman
2000) to induce LTP. For example, at neocortical layer 5 synapses the EPSP must
precede the postsynaptic action potential by a 10 ms interval to produce potentiation
(Fig. 5a–c), whereas a 100 ms interval produced no signal regardless of the order.
Interestingly, exactly synchronous pairing seems to be not effective in inducing
potentiation (Debanne et al. 1998). Other factors such as the inactivation of dendritic
K+ channels by the EPSP or the activation of Na+ channels by the cooperative EPSP-
AP pairing may contribute to synaptic efficacy (Magee and Johnston 1997). This
interaction boosts “action potential backpropagation” also in distal dendrites but in a
much narrower time window (Stuart and Häusser 2001; Sjöström and Häusser
2006). STDP seems to require detection of postsynaptic action potentials by synap-
ses and backpropagation of action potentials into the dendrite.
If the order is reverse to AP-EPSP pairing, LTP is not induced, but could produce
depression of paired synapses (Markram et al. 1997; Debanne et al. 1998; Zhang
et al. 1998; Egger et al. 1999; Feldman 2000, see also Fig. 5d–f). It should be noted
that the switch from maximal potentiation to depression (LTD) may occur within
<5 ms. In addition, spike pairing with random temporal ordering have also been
observed to generate LTD (Debanne et al. 1994; Feldman 2000). Synaptic potenti-
ation is mediated by a large increase in internal [Ca2+] while LTD follows from a
smaller sustained increase in [Ca2+] levels. Ca2+ imaging suggest that [Ca2+] in
ubke
a b
Presyn APs
60mV 2mV
1.5mV
100ms 100ms
c EPSPs
EPSP amplitude (% of control)

250 EPSPs
EPSPs and APs
200
150
100
50
0 10 20 30 40 50 60
Time (min)
e
d Vm Pre
20mV
1mV
EPSPs
20mV
10ms
Vm post
Im post
f
2.5 pairing 0.5mV
EPSP amplitude (mV)
2.0 20ms
1.5
1.0
0.5
0.0
−10 0 10 20 30 40
Time (min)
Fig. 5 Simultaneous pre- and postsynaptic activity in synaptically coupled neurons induces an
increase in EPSPs. (a) Camera lucida reconstruction of a bidirectionally coupled pair of thick-tufted
layer-5 pyramidal neurons, where both neurons are pre- and postsynaptic to each other. Putative
synaptic contacts are marked by green dots and blue dots and are preferentially located at the basal
dendritic tree. The axon collaterals are given in blue for the cell drawn in red and in green for the cell
drawn in black. An average of 5.5 contacts are made per connection, and more than 80 % of
contacts are within 200 μm of the soma. (b) Characteristic synaptic response. A presynaptic burst of
APs (Pre. APs) evoked by a 100-ms current pulse (400 pA, upper left trace) evokes EPSPs in the
postsynaptic neuron (lower left trace); the mean unitary EPSPs before (black trace) and after pairing
(red trace) is shown in the upper right panel. (c) Synchronization of pre- and postsynaptic activity.
Each dot represents the amplitude of a single, test, AP-evoked EPSP shown as a percent of the
average control EPSP. Whole-cell recording was established ~3 min before time 0. After 10 min of
recording, bursts of EPSPs were evoked 10 times every 20 s (indicated by the bar labeled EPSPs).
Test EPSPs were continuously sampled every 4 s in between these bursts. After 20 min of recording,
a burst of postsynaptic APs was evoked during EPSPs (15 times every 20 s; indicated by bar labeled
spines becomes greater with forward when compared with backwards pairing
(Koester and Sakmann 1998; Nevian and Sakmann 2004). Simple forms of learning,
for example classical conditioning display associate and temporal effects analogous
to those of STDP. The temporal contingencies introduced by STDP imply that
neuronal systems or circuitries can spontaneously develop predictive encodings of
sensory stimuli on the basis of experience.
Dendritic Excitability and Synaptic Plasticity
Dendrites like axons contain voltage-gated Na+ (Nav1.1–Nav1.12) channels out of

which five subunits probably are expressed throughout the CNS (reviewed by
Trimmer and Rhodes 2004). Detailed studies describing the regional, cellular, and
subcellular distribution of these subunits are still lacking, but it was shown that a
high density was found in Nodes of Ranvier and the axon hillock, but some subunits
are also present in the somato-dendritic domain of various neuronal cell types
(reviewed by Trimmer and Rhodes 2004). K+ channels are the most diverse
voltage-gated ion channels with more then a dozen of subunits and are predomi-
nantly found in axon initial segments, presynaptic specializations and the plasma
membrane of dendritic spines and were found even at non-synaptic sites (Kollo
et al. 2006). Ca2+ channels of the L, N, P/Q, R and T-type are found throughout the
entire CNS. Functional studies reveal that N, P/Q and R-type Ca2+ currents mediate
transmitter release from internal Ca2+ stores whereas L- and T-type currents are
responsible for somato-dendritic Ca2+ influx. It has been shown that neurons, in
particular pyramidal cells, express Ca2+ domains at specific dendritic sites (Stuart
et al. 1997a; Schiller et al. 1998; Larkum et al. 2007, 2009; reviewed by Stuart
et al. 1997b). Voltage-gated ions channels are inserted in a neuron-type dependent
Fig. 5 (continued) EPSPs and APs). Note the significant amplification of the EPSP amplitude after
the pairing. (d–f) Pairing of pre- and postsynaptic activity in synaptically coupled excitatory
neurons of rat barrel cortex induces a long lasting decrease in EPSPs in L4 spiny stellate neurons.
(d) Reconstruction of a pair of synaptically coupled spiny stellate neurons in layer 4. The presyn-
aptic neuron is drawn in black and its axon in red; the postsynaptic neuron in green with its axon in
blue (only partially shown). Three representative putative, light microscopically identified, synaptic
contacts as indicated by the red dots. (e) Pairing protocol of pre- and postsynaptic activity in spiny
stellate neurons. Presynaptic APs are evoked at 20 Hz (top trace); EPSPs evoked by presynaptic
stimuli without pairing (second trace). A postsynaptic AP (third trace) is evoked 10 ms after each
presynaptic AP by current injection in the postsynaptic neuron (see bottom trace), so that the
postsynaptic AP coincides with the peak of the EPSP. AP trains comprised 5 APs. (f) Diagram
showing the distribution of EPSP amplitudes versus time. The pairing protocol was applied after
baseline recording for 12 min. The amplitude of individual EPSPs is plotted (red squares). The
average EPSP amplitude after pairing was measured after a steady state was reached (first solid
black line) and after LTD induction (second solid black line). Average traces from before (black
trace) and after pairing (red trace) are shown in the upper right panel (a–c with permission from
SciencePublisher taken from Markram et al. 1997) (d–f with permission from NatureNeuroscience
taken from Egger et al. 1999)
ubke
fashion. Their cell surface distribution seems to be as complex and as highly

regulated than that of neurotransmitter receptors and may therefore profoundly
change the function of dendrites in synaptic integration and plasticity. Action
potentials are initiated in the axon, but the presence of voltage-gated Na+ channels
throughout the dendritic tree (with a gradient distribution from proximal to distal
dendritic segments) promotes the propagation of currents backwards in the dendritic
tree, a phenomenon called “backpropagating action potentials.” These
“backpropagating action potentials” may serve to notify synapses along the dendritic
tree when a spike has been evoked in the axon. The fact that LTP can be induced
without postsynaptic firing suggest that the influence of “backpropagating action
potentials” on LTP is the depolarization of the NMDA receptor and the subsequent
amplification of NMDA-mediated Ca2+ influx (Koester and Sakmann 1998; Schiller
et al. 1998; Yuste et al. 1999; Nevian and Sakmann 2004). Blockade of postsynaptic
action potentials and/or their propagation into the dendrite can prevent LTP induc-
tion (Magee and Johnston 1997). Furthermore, AP-EPSP pairing can induce LTP
(Fig. 5b, c), but not pairing of EPSPs or prolonged depolarization of high-frequency
stimulation (Markram et al. 1997; Zhang et al. 1998). Thus subthreshold summation
of EPSPs cannot produce enough depolarization to open NMDA receptors sufficient
to generate potentiation.
A variety of mechanisms have been shown to modulate the spatial extent of
dendritic action potential invasion. Differential modulation of “backpropagating
action potentials” could limit or reinforce the associativity between certain synapses
on the basis of their density and location throughout the dendritic tree (Froemke
et al. 2005; Sjöström and Häusser 2006). In general, synapses located on the same
dendritic tree are likely to detect the same action potential signal, whereas synapses
on different branches experience distinct action potential signals. Furthermore,
action potentials typically not fully invade the dendritic tree; only synapses at
proximal parts would sense depolarization and potentiation and would therefore
form associations with each other, but not with those more distally located,
uninvaded synapses (Spruston et al. 1995a, b; Stuart et al. 1997a, b). Thus, similar
considerations may occur also for branch-specific regulation of “backpropagating
action potentials” which include branch point failures (Spruston et al. 1995a, b;
Magee and Johnston 1997), excitatory (Magee and Johnston 1997; Magee 1998) or
inhibitory inputs (Buzsáki et al. 1996; Tsubokawa and Ross 1996) and other factors
such as neuromodulatory transmitters etc.
In summary, STDP strongly depends on the magnitude and temporal dependence
of synaptic location (Fig. 5a). The induction of plasticity seems to be governed by
“backpropagating action potentials” together with the generation of dendritic Ca2+
spikes (Larkum et al. 2007, 2009; reviewed by Stuart et al. 1997b).
Synapse specificity refers to the requirement of an individual synapse to be
presynaptically activated to undergo potentiation during a conditioning stimulus.
Although several mechanisms for regulating the overall amount of synaptic inputs to
a cell may play an important role (Turrigiano et al. 1998; Turrigiano and Nelson
1998), synapse specificity has been often regarded as a pre-requisite for synaptically
induced cellular memory functions. According to the spine NMDA receptor model,
synapse specificity requires the release of presynaptic glutamate to bind and open
NMDA receptors. Non-activated synapses, even postsynaptically depolarized, but
without glutamate binding to NMDA receptors, show no NMDA receptor-mediated
Ca2+ influx. It is therefore believed that synapse specificity relies on the ability of the
postsynaptic dendrite to sense and localize the [Ca2+] signal. As already mentioned
NMDA receptors have an unusually high affinity to Ca2+ and are thought to
represent the principal pathway for rises in spine [Ca2+]; NMDA receptor activation
together with [Ca2+] activation are considered as coincidence detectors. The trans-
duction of Ca2+ signals into different forms of synaptic plasticity and the amplitude
and duration of [Ca2+] in spines governs whether potentiation (LTP) or depression
(LTD) will occur. A rise in postsynaptic [Ca2+] is required for LTP or LTD induction,
a decrease in Ca2+ entry can induce LTD (Egger et al. 1999). Chelation of Ca2+ by
intracellular buffers also prevents LTP induction (Malenka et al. 1988). It is widely
accepted that the main function of postsynaptic spines is to compartmentalize
diffusible molecules and to prevent their diffusion to other neighbouring synapses.
Compartmentalization of Ca2+ transients by spines have been demonstrated with
various imaging techniques. However, it is not clear to what extent compartmental-
ization would hold under different stimulus conditions (Svoboda et al. 1996; Häusser
and Roth 1997). Although the NMDA receptor is the main source of Ca2+ entry into
dendritic spines, also other sources exist, namely voltage-gated Ca2+ channels
(VGCC) and intracellular Ca2+ stores. Local uncaging of neurotransmitter increases
[Ca2+] in spines that could be blocked with various Ca2+ channel blockers (Schiller
et al. 1998). Blockers of Ca2+ release from internal stores dramatically reduce Ca2+
transients in spines (Emptage 1999; Mainen et al. 1999). However, the amount of
Ca2+ induced by NMDA receptors or by VGCC is of comparable magnitude
(Koester and Sakmann 1998). Thus “backpropagating action potentials” or even
local depolarization could mediate NMDA receptor-independent synaptic plasticity
although it seems most likely that both NMDA receptors and VGCC contribute to
the process of LTP induction in spines. Interestingly, it has been proposed whether a
second parallel pathway to the NMDA receptor might detect presynaptic activity.
Candidates for this are metabotropic glutamate receptors that are impermeable to
ions but directly activate second messenger pathways. However, their role in LTP
induction still remains controversial (Selig et al. 1995, but see Egger et al. 1999).
Taken together a variety of different mechanisms drive the induction, mainte-
nance, and modulation of structural dendritic plasticity. Ongoing research has to be
performed to further unravel the signal cascades underlying the various forms of
dendritic plasticity.
Structural Plasticity
The adult brain has been classically viewed as a fixed and stable structure and it has
been thought in the past that the stability in the dendritic configuration of neurons
and axonal connectivity is necessary for continuity of various functions of the brain,
including learning, memory and individuality. However, many lines of evidence
ubke
have demonstrated an enormous structural dynamic of the brain, not only during
development, but also in the adult. Numerous studies have shown structural changes
in both, the axonal and dendritic arborization in response to damage (lesions),
aberrant activity, differential experience, and to factors such as hormones (summa-
rized by Duneavsky and Woolley 2008). It has been demonstrated that lesion-
induced deafferentiation induce dendritic structural plasticity. Lesions in different
brain regions, including neocortex, hippocampus, cerebellum, thalamus and hypo-
thalamus, are capable to induce dendritic retraction, extension, and formation of new
branches. These studies are not only important to understand the reaction of the brain
to damage, but also help to define limitations for structural changes and as a
consequence also functional changes following structural refinement. These studies
demonstrated the capacity of the brain to act (restructure and rewire itself) when
challenged. More recently, with the advent of sophisticated in vivo and in vitro live
imaging microscopy together with the ability to activate subsets of synapses embed-
ded in specific neuronal microcircuits it has become possible to directly monitor
structural dendritic plasticity induced by stimulation protocols like LTP or LTD
(Fig. 6b, c).
Dendritic plasticity is naturally observed during development of neurons. Devel-
opmental studies using different in vivo and in vitro methods, including time-lapse
imaging and electrophysiological recordings combined with intracellular tracer
injections, have shown the dynamic outgrowth of dendrites (Niell and Smith 2004;
Niell et al. 2004; Lordkipanidze and Dunaevsky 2005). The different types of
neurons expand their dendritic tree with ongoing age, by adding new branches and
branchpoints. However, certain types of excitatory neurons rearrange their dendrites
by active retraction of specific branches as shown for certain types of pyramidal
neurons, untufted pyramidal neurons in layer 5 and 6 (Koester and O’Leary 1992;
Kasper et al. 1994) or spiny stellate neurons, which all start with a terminal tuft
arborization that is retracted after the establishment of the cortical layers replacing
the cortical plate (Radnikow et al., unpublished observation).
In contrast, subsequent experiments using the lipophilic dye DiI or transgenic
mice expressing green fluorescent protein in cortical neurons have shown that in
adulthood the branching and length of dendrites remained nearly unchanged when
imaged over long periods of time (Trachtenberg et al. 2002; Mizrahi and Katz 2003;
Holtmaat et al. 2005) although dendrites of GABAergic interneurons in the adult
neocortex are more dynamic (plastic) than pyramidal cells which are more stable
(Lee et al. 2006). Dendritic spines are the major target (input station) of excitatory
synaptic input from various sources. As shown above, dendritic spines are highly
dynamic structures displaying various shapes and size. Time-lapse microscopy of
dissociated neurons or in organotypic cell cultures revealed that dendritic spines and
filopodia emerge and retract from the dendrites within seconds or minutes (Dailey
and Smith 1996; Dunaevsky et al. 1999; Engert and Bonhoeffer 1999; Maletic-
Savatic et al. 1999; Portera-Cailliau et al. 2003, see also Fig. 6b): Beside transient
spines emerging and retracing, persisting spines also undergo dynamic changes in
the shape and size of spine necks and heads (Fischer et al. 1998; Dunaevsky
et al. 1999; Fig. 6a).
a
OVX + O
OVX + E
b −5 0 1 2 4 12 20 30 min
c
CFP LTP induction
−10 −5 0 5 10 15 20 25 30 min
Actin polymerization (red: polymerized; blue: depolymerized)
Fig. 6 Structural induced plasticity. (a) Estradiol specifically increases the density of dendritic
spines of apical oblique dendrites of CA1 pyramidal cells. Three-dimensional reconstruction of two
dendritic segments from serial electron micrographs of an ovarectomized rat, treated with oil
(OVX + O, upper panel) and an ovarectomized rat treated with estrodiol (OVX + E, lower
panel). The dendrites are given in gray, presynaptic inputs to spines are shown in the following
colors: single synapse boutons are blue, different-cell multiple synapse boutons are green, same-cell
multiple synapse boutons are yellow, and spines from other unfilled cells are orange. Note the
increase in dendritic spine and multiple synapse bouton density on the OVX + E dendrite, cluster-
ing of multiple synapse boutons, and that the vast majority of multiple synapse boutons are
different-cells (With permission of PNAS taken from Yankova et al. 2001). (b) Structural plasticity
of a dendritic spine following the induction of LTP imaged with two-photon microscopy. Glutamate
uncaging at time point 0 induces a long-term volume increase of a stimulated spine (red dot, second
image) (Taken from Miquel Bosch, see also http://www.youtube.com/watch?v=b33Z). (c) Tetanic
stimulation shifts F-actin/G-actin equilibrium toward F-actin and enlarges spine head in CA1
pyramidal neurons taken from organotypic slice cultures. The CA1 pyramidal neurons were
biolistically cotransfected with CFP- and YFP-actin at a ratio of 1:3 by replacing EGFP in EGFP-
actin with ECFP and an improved version of YFP (Venus). The figure shows the actin polymeri-
zation (red) and depolymerization (blue) together with the expansion of a dendritic spine after
induction of LTP (white triangle) at CFP excitation (upper panel) and YFP-CaMKII (merged
ubke
Subsequent in vivo imaging through a thinned skull or a cranial window over

several month on GFP-expressing pyramidal neurons support the findings in culture
that spines are highly mobile in young (2–10 week old) animals, but were reduced
with the age of the animals (Grutzendler et al. 2002; Trachtenberg et al. 2002;
Holtmaat et al. 2005). In addition, the number of persistent spines increased from
35 % in immature to 73 % in mature animals, although region-specific differences
(visual vs. somatosensory neocortex) was observed in the dynamic of emergence and
retraction of transient, and the number of persistent spines (Trachtenberg et al. 2002;
Holtmaat et al. 2005).
Very importantly, spine dynamics is thought to induce and facilitate the formation
of synapses (Ziv and Smith 1996; Korkotian and Segal 2001; Zito et al. 2004) even
when motility is reduced with age although spine motility even persists when
contacted by a presynaptic terminal (Dunaevsky et al. 2001; Konur and Yuste
2004a, b; Umeda et al. 2005). A potential mechanism for the downregulation in
spine motility might be the ensheatment of synaptic complexes by astrocytic pro-
cesses with ongoing maturation (Dunaevsky et al. 2001).
Experience Induced Structural Dendritic Plasticity
Dendritic structures, in particular dendritic spines, undergo severe alterations with

enhanced neuronal activity, induced by LTP or LTD. First attempts to correlate
structural plasticity on spines dates back 30 years ago using LTP and subsequent
electronmicroscopic (EM) analysis of spines and synapses of granule cells in the
dentate gyrus. As a result a significant widening and shortening of the spine neck
was observed accompanied by an increase in surface area of the spine head by
~50 % in the stimulated area (Van Harreveld and Fifková 1975; Fifková and Van
Harreveld 1977; Fifková and Anderson 1981, see also Fig. 6b) within minutes after
stimulation and lasting for several hours. Further studies have shown that after LTP
induction the number of large spines with concave heads increases (Desmond and
Levy 1983) as well as the number of perforated synapses with a discontinuous
postsynaptic density (Geinisman et al. 1991), although some studies did not found
large effects in spine dynamics (but see Chang and Greenough 1984).
A first indication of a large effect after LTP on spine number came from serial
sectioning and subsequent EM analysis (Trommald et al. 1996) showing an signif-
icant increase (30–50 %) not only in the number of spines, but also in the appearance
of bifurcated splitted spines although the significant increase in spine numbers was
not confirmed by another study by Sorra and Harris (1998). However, the major
drawback of these studies were the unequivocally identification of stimulated
Fig. 6 (continued) image, lower panel) imaged using Fluorescence Resonance Energy Transfer
(FRET) microscopy. Numbers represent time steps in minutes (With permission of
NaturePublishing taken and modified from Okamoto et al. 2004)
synapses. This was elegantly shown by a study by Toni et al. (1999) in which
stimulated synapses could be recognized by their content of calcium precipitates in
the spines. Following LTP, a significant increase in the number of presynaptic
boutons contacting multiple spines (MSBs) at the same dendrite accompanied also
by a transient increase in perforated synapses. The study together with data from
Engert and Bonhoeffer (1999), Fiala et al. (2002a), Knott et al. (2006) and Harris
et al. (2003) pointed to a role of LTP in the induction and formation of new spines.
More recent studies using single- or two photon microscopy combined with live
imaging of neurons intracellularly filled with a fluorescent marker (Engert and
Bonhoeffer 1999) or transfected with a fluorescent protein (Dunaevsky
et al. 1999), or virally transfected (Maletic-Savatic et al. 1999) or genetically
(Grutzendler et al. 2002; Trachtenberg et al. 2002) have supported and substantiated
the above findings with the advantage that the same dendrite or spine along individ-
ual dendrites can be monitored before and after induction of LTP or LTD (Fig. 6b, c).
Taken together, LTP induces an increase in spine size (Hosokawa et al. 1995; Lang
et al. 2004; Matsuzaki et al. 2004, see also Fig. 6b) and spine number (Engert and
Bonhoeffer 1999; Maletic-Savatic et al. 1999; Nägerl et al. 2004), while LTD can
induce the shrinkage of spines (Zhou et al. 2004) and/or spine retraction (Nägerl
et al. 2004). These stimulation induced changes in spine dimensions are likely to be
mediated by activity-dependent changes in actin polymerization (Fischer et al. 1998;
Okamoto et al. 2004; see also Fig. 6c).
Sensory Deprivation, Enriched Environment and Behavioral Training
Other methods have been used to study experience-induced changes in dendritic

plasticity. First dark rearing experiments have shown either a slight or no dramatic
effect on dendritic plasticity (Globus and Scheibel 1967), but in later studies changes
in dendritic branching pattern and reduced spine densities were observed (Valverde
1967; Borges and Berry 1976, 1978; see also Wallace and Bear 2004). Recent
studies using whisker trimming as an experimental paradigm found a ~40 %
decrease in filopodia and spine motility of layer 2/3 pyramidal neurons in barrel
cortex. However, this change was only observed during the critical period and was
compared with deprivation induces abnormal formation of sensory maps in layer 2/3
(Lendvai et al. 2000). In contrast, in visual cortex binocular deprivation led to a
significant increase of spine dynamics by ~60 %, but only at the peak of the critical
period even in animals with brief monocular deprivation (Majewska and Sur 2003;
Oray et al. 2004). No such changes were found in acute slices of dark-reared animals
(Konur and Yuste 2004a, b), but a decrease in spine dynamics was observed. The
interpretation of the different results by sensory deprivation is difficult, but could be
explained by differences in the developmental stage between sensory areas and the
experimental design.
Housing of experimental animals in an isolated versus an enriched environment
has shown that beside an increase in cortical weight and thickness also dendrites
undergo significant changes. An increased field size of cortical pyramidal cells, in
ubke
particular on terminal basal dendrites (Uylings et al. 1978) or differences in synapse

size and density (Diamond et al. 1975) were found in rats housed in an enriched
environment. This effect on structural dendritic plasticity was later confirmed also by
others (Connor et al. 1980; Green et al. 1983; Greenough et al. 1985).
Behavioral experiments where animals are trained and conditioned to a certain
task also showed significant changes in structural dendritic plasticity. In a reach for
food task an increase in the total dendritic length, number of oblique branches, and
the length of the terminal tufts of the apical dendritic tree of layer 5 pyramidal
neurons has been demonstrated (Greenough et al. 1985). This was followed by more
complex behavioral tasks where experimental animals underwent motor skill learn-
ing; within 5–10 days animals reached a maximum learning plateau. Stereological
analysis of synaptic connectivity of pyramidal cells in motor cortex revealed a
significant, training-induced 13 % increase in the synapse-to-neuron ratio (Kleim
et al. 1996). Interestingly, also GABAergic interneurons seem to undergo structural
dendritic plasticity. Local stellate neurons in the cerebellar cortex showed an increase
(15 %) of their dendritic arborization after motor skill learning when compared with
controls (Kleim et al. 1997). Nowadays numerous studies with spatial learning
paradigms like the water (Morris et al. 1986; O’Malley et al. 2000; Eyre
et al. 2003; Beltrán-Campos et al. 2011) and radial maze (Böhm et al. 2002; Deller
et al. 2003; reviewed by Leung 2009) where animals were confronted with a
complex and constantly changing environment were performed. In a variety of
brain regions including neocortex, hippocampus and cerebellum, structural dendritic
plasticity at different neuronal cell types was observed, however, with different
levels of dendritic as well as spine alterations.
Hormone Induced Structural Dendritic Plasticity
It is now well established that hormones, in particular estrogen is a powerful

regulator in synaptic connectivity and structural dendritic plasticity in the developing
(Woolley and Cohen 2002) and adult brain. In the adult brain, structural changes in a
variety of brain regions occur in response to fluctuating levels of estradiol in the
preoptic area, different nuclei of the hypothalamus, midbrain central nuclei, lateral
septum, and hippocampus (summarized by Duneavsky and Woolley 2008). In the rat
hyphothalamus estrogen induces effects on both axo-somatic and axo-dendritic input
to neurons (Matsumoto and Arai 1979; Garcia-Segura et al. 1986; Olmos et al. 1989)
an effect also observed in the preoptic area (Witkin et al. 1991; Langub et al. 1994).
Here, elevated levels of estrogen applied exogenously or during the estrous cycle
induce a significant decline in GABAergic synapses, axosomatic synapses decreased
by 50 % during the proestrus, estrus and increased again at the diestrus phase. Other
structural changes, such as the proliferation or retraction of glia processes in
response to fluctuating levels of estrogen have been described in supraoptic,
paraventricular, and hypothalamic nuclei (Garcia-Segura et al. 1994).
The effects of estradiol have also been observed to regulate the structure and
function of synapses in the CA1 subregion of the hippocampus. A lot of studies have
demonstrated that the density of dendritic spines and excitatory synapses undergo
severe changes by fluctuating levels of estradiol. Spine density increases during the
cycle, peaks shortly before the proestrus, with a rapid decline after 24 h with an
overall change during the estrus in spine density reaching ~30 %. Furthermore,
ovarectomy decreases the number of spines on CA1 pyramidal neurons; this effect
could be prevented and reversed by estradiol treatment (Woolley and McEwen
1993). Interestingly, this fluctuation of spine number is not accompanied by struc-
tural changes in the length and branching of dendrites or in the number of shaft
(inhibitory) synapses (Leranth et al. 2000, 2002; Adams et al. 2001; Hao et al. 2006).
The significant increase in spine densities during the cycle also is reflected in the
increase of so-called MSBs accounting for adding newly generated spines to already
existing presynaptic boutons (Woolley et al. 1996, see also Fig. 6a). Biocytin-
labeling of individual CA1 pyramidal cells has further shown that the estradiol-
induced increase in MSBs frequency occurred in MSBs that establish connections
with multiple neurons. This may indicate that excitatory synaptic connections are
highly synchronized during the estrus (Yankova et al. 2001). It has to be noted that
the increase in excitatory synaptic connections is followed by a transient reduction in
GABAergic synaptic transmission (Murphy et al. 1998). In vitro and in vivo studies
have shown that treatment with estradiol resulted in a dramatic decrease of glutamic
decaboxylase, the GABA-synthesizing enzyme followed by a reduction of miniature
IPSPs and an increase in miniature EPSPs in spiny neurons (Rudick and Woolley
2001, 2003). The significant increase in the number of dendritic spines and MSBs is
correlated with severe functional changes such as a decrease in the induction of
epileptiform activity, but an enhancement of NMDA-receptor mediated synaptic
plasticity. It was further implicated that the estradiol-induced effects on structural
and functional plasticity could also be directly linked to learning and memory, but
lead to differences in the performance of experimental animals in short-term spatial
memory tasks or to use a more “place” than “response strategy” in the Morris water
or radial maze dependent on the state of the estrus cycle.
Structural Pathology
Abnormalities in dendritic structural plasticity are a characteristic feature of many

mental, neurological and neurodegenerative brain disorders (summarized by Ber-
nard et al. 2008, see also Fig. 7). Changes in synaptic function or neuronal circuitry
associated with disease and mental retardation produce severe structural changes in
dendritic length and branching, dramatic loss of spines accompanied also by
changes in spine morphology. Dendritic and spine pathology have been described
for different mental disorders such as Down, Rett, fragile-X (Fig. 7c1–3), autism
(Fig. 7d1–6) and schizophrenia (Chapleau et al. 2009; Garcia et al. 2010; Van
Spronsen and Hoogenraad 2010; reviewed by Penzes et al. 2011, see also
Fig. 7b1–5).
A first evidence for pathology-induced structural dendritic plasticity came from
lesions-induced changes followed by deafferentiation and therefore loss of
ubke
a1 a2 c1 c2 c3
a3
d1 2 3
d4 5 6
b1 b2 b3 b4 b5
Fig. 7 Dendritic pathology induced by neurological and neurodegenerative disorders. (a1, a2),
Golgi-impregnated cerebellar Purkinje neurons in a normal (a1) and Alzheimer (a2) brain (With
courtesy from Ronald F. Mervis, Neurostructural Research Laboratories, Inc., Tampa, FL 33637
USA; Website: www.neurostructural.org). (a3), Low magnification of the CA1 subregion of the
hippocampus in a human Alzheimer brain. Note the severe changes in the overall dendritic
structure, branching and density of spines (Neurodigitech) (Taken from http://www.golgistain.
com/Services.php). (b1–b3), Golgi-impregnated basal dendrites and spines of layer 3 pyramidal
neurons in the dorsolateral prefrontal cortex from a normal control subjects (b1) and two subjects
with schizophrenia (b2 and b3) (Adapted and modified from Archives of General Psychiatry
57:65–73). (b4, b5), Type III Nrg1 heterozygous mice, a mouse model for schizophrenia, show
significant alterations in dendritic structure, branching, and a severe decrease in spine density within
proximal regions of apical dendrites of hippocampal pyramidal neurons (b5) compared to wild type
littermates (b4) as also found in the human brain (b2, b3) (With permission Journal of Neuroscience
taken and modified from Chen et al. (2008)). (c1–c3), In Fragile X mental retardation, the lack of the
fragile-X mental retardation protein (FMRP) causes an overproduction of dendritic spines. FMRP
normally acts as a “brake” on synapse generation, balancing the “accelerator” effects of mGluR5.
Dendrites from a “wild-type” mouse (c1); from the Fragile X knock-out mouse, which lacks FMRP
synaptic input. This led to profound reduction, deformation and disorientation of

dendrites in cerebellar Purkinje cells (Altman and Bayer 1997). Lesion-induced
dendritic changes, a significant reduction in the length of distal dendrites, were also
observed in dentate gyrus granule cells following deafferentiation of the entorhinal
cortex. Interestingly, a reverse effect, dendritic and mossy fiber sprouting of basal
dendrites of hippocampal granule cells can be induce by sustained epileptiform
activity (Buckmaster and Dudek 1999; Ribak et al. 2000).
A number of progressive neurodegenerative disorders are associated with forms
of dendrite pathologies (reviewed by Fiala et al. 2002b). A particular aggregation of
proteins in dendrites, so-called Lewy bodies are observed in Parkinson disease
(Hirano 1981). In Jakob-Creutzfeldt, a form of prionosis, vacuolar dystrophy with
dendrites causes a spongiform appearance of the neuropil. Similar observations on
abnormal dendritic and synaptic changes, but also accompanied by a loss and
pathological changes in spine shape and size were observed in Alzheimer’s disease
(Fig. 7a1–3; see also Falke et al. 2003; Scheff and Price 2003), schizophrenia
(Fig. 7b1–5; see also Black et al. 2004), fragile-X (Fig. 7c1–3; see also Pfeiffer
and Huber 2007; Cruz-Martin et al. 2010; reviewed by van Van Spronsen and
Hoogenraad 2010) and autism (Fig. 7d1–6; see also Hutsler and Zhang 2010;
reviewed by Boda et al. 2010). This pathologically induced structural dendritic
plasticity is directly correlated with severe dysfunctions in synaptic transmission,
strength, efficacy and plasticity, the underlying mechanisms for learning and mem-
ory functions (Meredith and Mansvelder 2010).
Taken together, a variety of different approaches have demonstrated structural
plasticity in the developing and adult brain, particularly in dendrites, dendritic spines
and their associated synaptic inputs. Whether structural dendritic and synaptic
plasticity is a general mechanism for the nervous system to react, for example to
environmental changes or disease has to be further investigated. Several important
mouse models for different brain disorders are now available and should provide
future perspectives to investigate brain pathologies at the cellular, dendritic, subcel-
lular, and synaptic level.
Fig. 7 (continued) (c2), and from the Fragile-X knock-out mouse after mGluR5 has been reduced
(c3). The increased density of spines in the Fragile-X knock-out is rescued to wild-type levels by
reducing mGluR5 (From Dölen et al. 2007 with courtesy from Mark F. Bear, Picower Institute for
Learning and Memory MIT and Howard Hughes Medical Institute Cambridge, 02139 MA, USA).
(d1–d6), Mice deficient for the UBE3A gene product E6-AP (AS), a mouse model for autism,
display abnormal dendritic spine morphologies. Light microscopic images from Golgi-impregnated
Purkinje cells in wild type (d1) and AS mice (d4), hippocampal CA1 pyramidal neurons (d2, d5)
and cortical layer 2/3 pyramidal neurons (d3, d6). AS mice exhibited abnormal, reduced dendritic
spine density on cerebellar, hippocampal and cortical neurons, despite a normal cellular architecture
and dendritic branching when compare with the wild type. In addition, AS mice had swellings
(black arrowhead) along secondary apical dendrites (With permission from Oxford University
Press taken from Dindot et al. (2008))
ubke
Outlook
Dendrites, the input structure of a neuron, receive, integrate and modulate incoming
signals from the sensory periphery. Their aborization pattern together with their size
not only determines the mode of connectivity between neurons in a given network but
also the formation of highly specific spatial domains where they receive specific input.
Although the term “dendrites” is as old as the first complete description of a
neuron it was the introduction of state-of-the-art technology in the field of neurosci-
ence to unravel the hidden secrets of dendrites. At the structural level, for example,
in vivo and in vitro high-end light-, STED (Stimulated Emission Depletion) and
TIRF (Total internal reflection) fluorescence microscopy, confocal, two-photon and
electron microscopy allowed new insights into dendritic information processing at
high resolution in the micrometer to nanometer range. Differential interference
contrast video microscopy in combination with simultaneous patch-clamping of
different dendritic segments made it possible to study dendritic integration of signals
in vitro. The combination of two-photon, STED- and TIRF microcopy in combina-
tion with molecular approaches, for example tagging of various proteins expressed
in dendrites by green fluorescent protein made it possible to study the internal
machinery of dendrites or the detection of Ca2+ in the smallest dendritic compart-
ment, the spine, further investigate structural and functional aspects of dendritic
information processing, storage and integration. However, further research and
technical developments will be necessary to unravel the last secrets of dendrites.
References
Abbott LF, Nelson SB (2000) Synaptic plasticity: taming the beast. Nat Neurosci
3(Suppl):1178–1183
Adams MM, Shah RA, Janssen WG, Morrison JH (2001) Different modes of hippocampal
plasticity in response to estrogen in young and aged female rats. Proc Natl Acad Sci U S A
98:8071–8076
Altman J, Bayer S (1997) Development of the cerebellar system in relation to its evolution,
structure, and functions. CRC Press, Boca Raton
Ascher P, Nowak L (1988) The role of divalent cations in the N-methyl-d-aspartate responses of
mouse central neurones in culture. J Physiol 399:247–266
Barrionuevo G, Brown TH (1983) Associative long-term potentiation in hippocampal slices. Proc
Natl Acad Sci U S A 80:7347–7351
Baude A, Nusser Z, Molnar E, McIlhinney RA, Somogyi P (1995) High-resolution immunogold
localization of AMPA type glutamate receptor subunits at synaptic and non-synaptic sites in rat
hippocampus. Neuroscience 69:1031–1055
Bear MF, Kirkwood A (1993) Neocortical long-term potentiation. Curr Opin Neurobiol 3:197–202
Bear MF, Malenka RC (1994) Synaptic plasticity: LTP and LTD. Curr Opin Neurobiol 4:389–399
Beltran-Campos V, Prado-Alcala RA, Leon-Jacinto U, Aguilar-Vazquez A, Quirarte GL, Ramirez-
Amaya V, Diaz-Cintra S (2011) Increase of mushroom spine density in CA1 apical dendrites
produced by water maze training is prevented by ovariectomy. Brain Res 1369:119–130
Bergles DE, Dzubay JA, Jahr CE (1997) Glutamate transporter currents in Bergmann glial cells
follow the time course of extrasynaptic glutamate. Proc Natl Acad Sci U S A 94:14821–14825
Bernard C, Shah M, Johnston D (2008) Dendrites and disease, Chapter 20. In: Stuart G et al (eds)
Dendrites, 2nd edn. Oxford University Press, New York, pp 531–554
Black JE, Kodish IM, Grossman AW, Klintsova AY, Orlovskaya D, Vostrikov V, Uranova N,
Greenough WT (2004) Pathology of layer V pyramidal neurons in the prefrontal cortex of
patients with schizophrenia. Am J Psychiatry 161:742–744
Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the
hippocampus. Nature 361:31–39
Bliss TV, LomØ T (1973) Long-lasting potentiation of synaptic transmission in the dentate area
of the anaesthetized rabbit following stimulation of the perforant path. J Physiol 232:331–356
Boda B, Dubos A, Muller D (2010) Signaling mechanisms regulating synapse formation and
function in mental retardation. Curr Opin Neurobiol 20:519–527
Böhm D, Schwegler H, Kotthaus L, Nayernia K, Rickmann M, Kohler M, Rosenbusch J, Engel W,
Fl€
ugge G, Burfeind P (2002) Disruption of PLC-beta 1-mediated signal transduction in mutant
mice causes age-dependent hippocampal mossy fiber sprouting and neurodegeneration. Mol
Cell Neurosci 21:584–601
Borges S, Berry M (1976) Preferential orientation of stellate cell dendrites in the visual cortex of the
dark-reared rat. Brain Res 112:141–147
Borges S, Berry M (1978) The effects of dark rearing on the development of the visual cortex of the
rat. J Comp Neurol 180:277–300
Buckmaster PS, Dudek FE (1999) In vivo intracellular analysis of granule cell axon reorganization
in epileptic rats. J Neurophysiol 81:712–721
Buzsáki G, Penttonen M, Nadasdy Z, Bragin A (1996) Pattern and inhibition-dependent invasion of
pyramidal cell dendrites by fast spikes in the hippocampus in vivo. Proc Natl Acad Sci U S A
93:9921–9925
Chang FL, Greenough WT (1984) Transient and enduring morphological correlates of synaptic
activity and efficacy change in the rat hippocampal slice. Brain Res 309:35–46
Chapleau CA, Calfa GD, Lane MC, Albertson AJ, Larimore JL, Kudo S, Armstrong DL, Percy AK,
Pozzo-Miller L (2009) Dendritic spine pathologies in hippocampal pyramidal neurons from Rett
syndrome brain and after expression of Rett-associated MECP2 mutations. Neurobiol Dis
35:219–233
Chen YJ, Johnson MA, Lieberman MD, Goodchild RE, Schobel S, Lewandowski N, Rosoklija G,
Liu RC, Gingrich JA, Small S, Moore H, Dwork AJ, Talmage DA, Role LW (2008) Type III
neuregulin-1 is required for normal sensorimotor gating, memory-related behaviors, and
corticostriatal circuit components. J Neurosci 28:6872–6883
Chicurel ME, Harris KM (1992) Three-dimensional analysis of the structure and composition of
CA3 branched dendritic spines and their synaptic relationships with mossy fiber boutons in the
rat hippocampus. J Comp Neurol 325:169–182
Chklovskii DB, Mel BW, Svoboda K (2004) Cortical rewiring and information storage. Nature
431:782–788
Colino A, Huang YY, Malenka RC (1992) Characterization of the integration time for the stabili-
zation of long-term potentiation in area CA1 of the hippocampus. J Neurosci 12:180–187
Colonnier M (1968) Synaptic patterns on different cell types in the different laminae of the cat
visual cortex. An electron microscope study. Brain Res 9:268–287
Connor JR Jr, Diamond MC, Johnson RE (1980) Aging and environmental influences on two types
of dendritic spines in the rat occipital cortex. Exp Neurol 70:371–379
Cooney JR, Hurlburt JL, Selig DK, Harris KM, Fiala JC (2002) Endosomal compartments serve
multiple hippocampal dendritic spines from a widespread rather than a local store of recycling
membrane. J Neurosci 22:2215–2224
Cruz-Martin A, Crespo M, Portera-Cailliau C (2010) Delayed stabilization of dendritic spines in
fragile X mice. J Neurosci 30:7793–7803
Dailey ME, Smith SJ (1996) The dynamics of dendritic structure in developing hippocampal slices.
J Neurosci 16:2983–2994
Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105
ubke
Davies CH, Collingridge GL (1996) Regulation of EPSPs by the synaptic activation of GABAB
autoreceptors in rat hippocampus. J Physiol 496(Pt 2):451–470
Debanne D, Gahwiler BH, Thompson SM (1994) Asynchronous pre- and postsynaptic activity
induces associative long-term depression in area CA1 of the rat hippocampus in vitro. Proc Natl
Acad Sci U S A 91:1148–1152
Debanne D, Gahwiler BH, Thompson SM (1998) Long-term synaptic plasticity between pairs of
individual CA3 pyramidal cells in rat hippocampal slice cultures. J Physiol 507:237–247
DeFelipe J, Farinas I (1992) The pyramidal neuron of the cerebral cortex: morphological and
chemical characteristics of the synaptic inputs. Prog Neurobiol 39:563–607
Deller T, Korte M, Chabanis S, Drakew A, Schwegler H, Stefani GG, Zuniga A, Schwarz K,
Bonhoeffer T, Zeller R, Frotscher M, Mundel P (2003) Synaptopodin-deficient mice lack a spine
apparatus and show deficits in synaptic plasticity. Proc Natl Acad Sci U S A 100:10494–10499
Desmond NL, Levy WB (1983) Synaptic correlates of associative potentiation/depression: an
ultrastructural study in the hippocampus. Brain Res 265:21–30
Diamond MC, Lindner B, Johnson R, Bennett EL, Rosenzweig MR (1975) Differences in occipital
cortical synapses from environmentally enriched, impoverished, and standard colony rats.
J Neurosci Res 1:109–119
Dindot SV, Antalffy BA, Bhattacharjee MB, Beaudet AL (2008) The Angelman syndrome ubiquitin
ligase localizes to the synapse and nucleus, and maternal deficiency results in abnormal dendritic
spine morphology. Hum Mol Genet 17:111–118
Dölen G, Osterweil E, Shankaranarayana Rao BS, Smith GB, Auerbach BD, Chattarji S, Bear MF
(2007) Correction of fragile X syndrome in mice. Neuron 56:955–962
Dunaevsky A, Tashiro A, Majewska A, Mason C, Yuste R (1999) Developmental regulation of
spine motility in the mammalian central nervous system. Proc Natl Acad Sci U S A
96:13438–13443
Dunaevsky A, Blazeski R, Yuste R, Mason C (2001) Spine motility with synaptic contact. Nat
Neurosci 4:685–686
Duneavsky A, Woolley CS (2008) Structural plasticity of dendrites, Chapter 19. In: Stuart G
et al (eds) Dendrites, 2nd edn. Oxford University Press, New York, pp 499–530
Eberhard JP, Wanner A, Wittum G (2006) NeuGen: A tool for the generation of realistic morphol-
ogy of cortical neurons and neural networks in 3D. Neurocomputing 70(1–3):327–342
Egger V, Feldmeyer D, Sakmann B (1999) Coincidence detection and changes of synaptic efficacy
in spiny stellate neurons in rat barrel cortex. Nat Neurosci 2:1098–1105
Ellias SA, Stevens JK (1980) The dendritic varicosity: a mechanism for electrically isolating the
dendrites of cat retinal amacrine cells? Brain Res 196:365–372
Emptage NJ (1999) Calcium on the up: supralinear calcium signaling in central neurons. Neuron
24:495–497
Engert F, Bonhoeffer T (1999) Dendritic spine changes associated with hippocampal long-term
synaptic plasticity. Nature 399:66–70
Eyre MD, Richter-Levin G, Avital A, Stewart MG (2003) Morphological changes in hippocampal
dentate gyrus synapses following spatial learning in rats are transient. Eur J Neurosci
17:1973–1980
Falke E, Nissanov J, Mitchell TW, Bennett DA, Trojanowski JQ, Arnold SE (2003) Subicular
dendritic arborization in Alzheimer’s disease correlates with neurofibrillary tangle density. Am J
Pathol 163:1615–1621
Feldman ML (1984) Morphology oft he neocortical pyramidal neuron. In: Peters A, Jones EG (eds)
Cerebral cortex, vol 1. Plenum Press, New York, pp 123–200
Feldman DE (2000) Timing-based LTP and LTD at vertical inputs to layer II/III pyramidal cells in
rat barrel cortex. Neuron 27:45–56
Fiala JC, Feinberg M, Popov V, Harris KM (1998) Synaptogenesis via dendritic filopodia in
developing hippocampal area CA1. J Neurosci 18:8900–8911
Fiala JC, Allwardt B, Harris KM (2002a) Dendritic spines do not split during hippocampal LTP or
maturation. Nat Neurosci 5:297–298
Fiala JC, Spacek J, Harris KM (2002b) Dendritic spine pathology: cause or consequence of
neurological disorders? Brain Res Brain Res Rev 39:29–54
Fiala JC, Kirov SA, Feinberg MD, Petrak LJ, George P, Goddard CA, Harris KM (2003) Timing of
neuronal and glial ultrastructure disruption during brain slice preparation and recovery in vitro.
J Comp Neurol 465:90–103
Fiala JC, Spacek J, Harris KM (2008) Dendritc structure, Chapter 1. In: Stuart G et al (eds)
Dendrites, 2nd edn. Oxford University Press, New York, pp 1–41
Fifková E (1985a) Actin in the nervous system. Brain Res 356:187–215
Fifková E (1985b) A possible mechanism of morphometric changes in dendritic spines induced by
stimulation. Cell Mol Neurobiol 5:47–63
Fifková E, Anderson CL (1981) Stimulation-induced changes in dimensions of stalks of dendritic
spines in the dentate molecular layer. Exp Neurol 74:621–627
Fifková E, Van Harreveld A (1977) Long-lasting morphological changes in dendritic spines of
dentate granular cells following stimulation of the entorhinal area. J Neurocytol 6:211–230
Fischer M, Kaech S, Knutti D, Matus A (1998) Rapid actin-based plasticity in dendritic spines.
Neuron 20:847–854
Freund TF, Buzsáki G (1996) Interneurons of the hippocampus. Hippocampus 6:347–470
Froemke RC, Poo MM, Dan Y (2005) Spike-timing-dependent synaptic plasticity depends on
dendritic location. Nature 434:221–225
Garcia O, Torres M, Helguera P, Coskun P, Busciglio J (2010) A role for thrombospondin-1 deficits
in astrocyte-mediated spine and synaptic pathology in Down’s syndrome. PLoS One 5, e14200
Garcia-Segura LM, Baetens D, Naftolin F (1986) Synaptic remodelling in arcuate nucleus after
injection of estradiol valerate in adult female rats. Brain Res 366:131–136
Garcia-Segura LM, Chowen JA, Parducz A, Naftolin F (1994) Gonadal hormones as promoters of
structural synaptic plasticity: cellular mechanisms. Prog Neurobiol 44:279–307
Geinisman Y, deToledo-Morrell L, Morrell F (1991) Induction of long-term potentiation is associ-
ated with an increase in the number of axospinous synapses with segmented postsynaptic
densities. Brain Res 566:77–88
Globus A, Scheibel AB (1967) The effect of visual deprivation on cortical neurons: a Golgi study.
Exp Neurol 19:331–345
Gray EG (1959) Electron microscopy of synaptic contacts on dendrite spines of the cerebral cortex.
Nature 183:1592–1593
Green EJ, Greenough WT, Schlumpf BE (1983) Effects of complex or isolated environments on
cortical dendrites of middle-aged rats. Brain Res 264:233–240
Greenough WT, Larson JR, Withers GS (1985) Effects of unilateral and bilateral training in a
reaching task on dendritic branching of neurons in the rat motor-sensory forelimb cortex. Behav
Neural Biol 44:301–314
Grutzendler J, Kasthuri N, Gan WB (2002) Long-term dendritic spine stability in the adult cortex.
Nature 420:812–816
Gupta A, Wang Y, Markram H (2000) Organizing principles for a diversity of GABAergic
interneurons and synapses in the neocortex. Science 287:273–278
Halpain S, Hipolito A, Saffer L (1998) Regulation of F-actin stability in dendritic spines by
glutamate receptors and calcineurin. J Neurosci 18:9835–9844
Hamlyn LH (1962) The fine structure of the mossy fiber endings in the hippocampus of the rabbit.
J Anat 96:112–120
Hao J, Rapp PR, Leffler AE, Leffler SR, Janssen WG, Lou W, McKay H, Roberts JA, Wearne SL,
Hof PR, Morrison JH (2006) Estrogen alters spine number and morphology in prefrontal cortex
of aged female rhesus monkeys. J Neurosci 26:2571–2578
Harris KM, Stevens JK (1988) Dendritic spines of rat cerebellar Purkinje cells: serial electron
microscopy with reference to their biophysical characteristics. J Neurosci 8:4455–4469
Harris KM, Jensen FE, Tsao B (1992) Three-dimensional structure of dendritic spines and synapses
in rat hippocampus (CA1) at postnatal day 15 and adult ages: implications for the maturation of
synaptic physiology and long-term potentiation. J Neurosci 12:2685–2705
ubke
Harris KM, Fiala JC, Ostroff L (2003) Structural changes at dendritic spine synapses during long-
term potentiation. Philos Trans R Soc Lond B Biol Sci 358:745–748
Häusser M, Clark BA (1997) Tonic synaptic inhibition modulates neuronal output pattern and
spatiotemporal synaptic integration. Neuron 19:665–678
Häusser M, Roth A (1997) Estimating the time course of the excitatory synaptic conductance in
neocortical pyramidal cells using a novel voltage jump method. J Neurosci 17:7606–7625
Hebb DO (1949) The organization of behaviour. Wiley, New York
Helmstaedter M, Sakmann B, Feldmeyer D (2009a) L2/3 interneuron groups defined by
multiparameter analysis of axonal projection, dendritic geometry, and electrical excitability.
Cereb Cortex 19:951–962
Helmstaedter M, Sakmann B, Feldmeyer D (2009b) The relation between dendritic geometry,
electrical excitability, and axonal projections of L2/3 interneurons in rat barrel cortex. Cereb
Cortex 19:938–950
Hirano A (1981) A guide to neuropathology. Igaku Shoin, New York/Tokyo
Holtmaat AJ, Trachtenberg JT, Wilbrecht L, Shepherd GM, Zhang X, Knott GW, Svoboda K (2005)
Transient and persistent dendritic spines in the neocortex in vivo. Neuron 45:279–291
Hosokawa T, Rusakov DA, Bliss TV, Fine A (1995) Repeated confocal imaging of individual
dendritic spines in the living hippocampal slice: evidence for changes in length and orientation
associated with chemically induced LTP. J Neurosci 15:5560–5573
Hutsler JJ, Zhang H (2010) Increased dendritic spine densities on cortical projection neurons in
autism spectrum disorders. Brain Res 1309:83–94
Johnston D, Williams S, Jaffe D, Gray R (1992) NMDA-receptor-independent long-term potenti-
ation. Annu Rev Physiol 54:489–505
Kampa BM, Clements J, Jonas P, Stuart GJ (2004) Kinetics of Mg2+ unblock of NMDA receptors:
implications for spike-timing dependent synaptic plasticity. J Physiol 556:337–345
Kasper EM, L€ ubke J, Larkman AU, Blakemore C (1994) Pyramidal neurons in layer 5 of the rat
visual cortex. III. Differential maturation of axon targeting, dendritic morphology, and electro-
physiological properties. J Comp Neurol 339:495–518
Kelso SR, Ganong AH, Brown TH (1986) Hebbian synapses in hippocampus. Proc Natl Acad Sci
U S A 83:5326–5330
Kharazia VN, Weinberg RJ (1999) Immunogold localization of AMPA and NMDA receptors in
somatic sensory cortex of albino rat. J Comp Neurol 412:292–302
Kleim JA, Lussnig E, Schwarz ER, Comery TA, Greenough WT (1996) Synaptogenesis and Fos
expression in the motor cortex of the adult rat after motor skill learning. J Neurosci
16:4529–4535
Kleim JA, Swain RA, Czerlanis CM, Kelly JL, Pipitone MA, Greenough WT (1997) Learning-
dependent dendritic hypertrophy of cerebellar stellate cells: plasticity of local circuit neurons.
Neurobiol Learn Mem 67:29–33
Knott GW, Holtmaat A, Wilbrecht L, Welker E, Svoboda K (2006) Spine growth precedes synapse
formation in the adult neocortex in vivo. Nat Neurosci 9:1117–1124
Koester SE, O’Leary DD (1992) Functional classes of cortical projection neurons develop dendritic
distinctions by class-specific sculpting of an early common pattern. J Neurosci 12:1382–1393
Koester HJ, Sakmann B (1998) Calcium dynamics in single spines during coincident pre- and
postsynaptic activity depend on relative timing of back-propagating action potentials and
subthreshold excitatory postsynaptic potentials. Proc Natl Acad Sci U S A 95:9596–9601
Kollo M, Holderith NB, Nusser Z (2006) Novel subcellular distribution pattern of A-type K+
channels on neuronal surface. J Neurosci 26:2684–2691
Konur S, Yuste R (2004a) Imaging the motility of dendritic protrusions and axon terminals: roles in
axon sampling and synaptic competition. Mol Cell Neurosci 27:427–440
Konur S, Yuste R (2004b) Developmental regulation of spine and filopodial motility in primary
visual cortex: reduced effects of activity and sensory deprivation. J Neurobiol 59:236–246
Korkotian E, Segal M (2001) Regulation of dendritic spine motility in cultured hippocampal
neurons. J Neurosci 21:6115–6124
Lang C, Barco A, Zablow L, Kandel ER, Siegelbaum SA, Zakharenko SS (2004) Transient
expansion of synaptically connected dendritic spines upon induction of hippocampal long-
term potentiation. Proc Natl Acad Sci U S A 101:16665–16670
Langub MC Jr, Maley BE, Watson RE Jr (1994) Estrous cycle-associated axosomatic synaptic
plasticity upon estrogen receptive neurons in the rat preoptic area. Brain Res 641:303–310
Larkman AU (1991) Dendritic morphology of pyramidal neurones of the visual cortex of the rat: III.
Spine distributions. J Comp Neurol 306:332–343
Larkman A, Mason A (1990) Correlations between morphology and electrophysiology of pyrami-
dal neurons in slices of rat visual cortex. I. Establishment of cell classes. J Neurosci
10:1407–1414
Larkum ME, Waters J, Sakmann B, Helmchen F (2007) Dendritic spikes in apical dendrites of
neocortical layer 2/3 pyramidal neurons. J Neurosci 27:8999–9008
Larkum ME, Nevian T, Sandler M, Polsky A, Schiller J (2009) Synaptic integration in tuft dendrites
of layer 5 pyramidal neurons: a new unifying principle. Science 325:756–760
Lee WC, Huang H, Feng G, Sanes JR, Brown EN, So PT, Nedivi E (2006) Dynamic remodeling of
dendritic arbors in GABAergic interneurons of adult visual cortex. PLoS Biol 4, e29
Lendvai B, Stern EA, Chen B, Svoboda K (2000) Experience-dependent plasticity of dendritic
spines in the developing rat barrel cortex in vivo. Nature 404:876–881
Leranth C, Shanabrough M, Horvath TL (2000) Hormonal regulation of hippocampal spine synapse
density involves subcortical mediation. Neuroscience 101:349–356
Leranth C, Shanabrough M, Redmond DE Jr (2002) Gonadal hormones are responsible for
maintaining the integrity of spine synapses in the CA1 hippocampal subfield of female
nonhuman primates. J Comp Neurol 447:34–42
Leung LS (2009) Kindling, long-term potentiation and spatial memory performance. Can J Neurol
Sci 36(Suppl 2):S36–S38
Levy WB, Steward O (1983) Temporal contiguity requirements for long-term associative potenti-
ation/depression in the hippocampus. Neuroscience 8:791–797
Lordkipanidze T, Dunaevsky A (2005) Purkinje cell dendrites grow in alignment with Bergmann
glia. Glia 51:229–234
Lujan R, Shigemoto R, Lopez-Bendito G (2005) Glutamate and GABA receptor signalling in the
developing brain. Neuroscience 130:567–580
Maccaferri G, Tóth K, McBain CJ (1998) Target-specific expression of presynaptic mossy fiber
plasticity. Science 279:1368–1370
MacDermott AB, Mayer ML, Westbrook GL, Smith SJ, Barker JL (1986) NMDA-receptor
activation increases cytoplasmic calcium concentration in cultured spinal cord neurones. Nature
321:519–522
Magee JC (1998) Dendritic hyperpolarization-activated currents modify the integrative properties
of hippocampal CA1 pyramidal neurons. J Neurosci 18:7613–7624
Magee JC, Johnston D (1997) A synaptically controlled, associative signal for Hebbian plasticity in
hippocampal neurons. Science 275:209–213
Mainen ZF, Abott LF (2008) Functional plasticity at dendritic synapses, Chapter 18. In: Stuart G
et al (eds) Dendrites, 2nd edn. Oxford University Press, New York, pp 465–498
Mainen ZF, Malinow R, Svoboda K (1999) Synaptic calcium transients in single spines indicate that
NMDA receptors are not saturated. Nature 399:151–155
Majewska A, Sur M (2003) Motility of dendritic spines in visual cortex in vivo: changes during
the critical period and effects of visual deprivation. Proc Natl Acad Sci U S A 100:
16024–16029
Malenka RC, Kauer JA, Zucker RS, Nicoll RA (1988) Postsynaptic calcium is sufficient for
potentiation of hippocampal synaptic transmission. Science 242:81–84
Maletic-Savatic M, Malinow R, Svoboda K (1999) Rapid dendritic morphogenesis in CA1 hippo-
campal dendrites induced by synaptic activity. Science 283:1923–1927
Malinow R, Miller JP (1986) Postsynaptic hyperpolarization during conditioning reversibly blocks
induction of long-term potentiation. Nature 320:529–530
ubke
Markram H, L€ ubke J, Frotscher M, Sakmann B (1997) Regulation of synaptic efficacy by coinci-

dence of postsynaptic APs and EPSPs. Science 275:213–215
Martinez JL, Derrick BE (1996) Long-term potentiation and learning. Annu Rev Psychol
47:173–203
Mason A, Larkman A (1990) Correlations between morphology and electrophysiology of pyrami-
dal neurons in slices of rat visual cortex. II. Electrophysiology. J Neurosci 10:1415–1428
Matsumoto A, Arai Y (1979) Synaptogenic effect of estrogen on the hypothalamic arcuate nucleus
of the adult female rat. Cell Tissue Res 198:427–433
Matsuzaki M, Honkura N, Ellis-Davies GC, Kasai H (2004) Structural basis of long-term poten-
tiation in single dendritic spines. Nature 429:761–766
McBain CJ, Mayer ML (1994) N-methyl-d-aspartic acid receptor structure and function. Physiol
Rev 74:723–760
McNaughton BL, Douglas RM, Goddard GV (1978) Synaptic enhancement in fascia dentata:
cooperativity among coactive afferents. Brain Res 157:277–293
Mehta MR (2004) Cooperative LTP can map memory sequences on dendritic branches. Trends
Neurosci 27:69–72
Mel BW (1993) Synaptic integration in an excitable dendritic tree. J Neurophysiol 70:1086–1101
Mel BW (1994) Information processing in dendritic trees. Neural Comput 6:1031–1085
Meredith RM, Mansvelder HD (2010) STDP and mental retardation: dysregulation of dendritic
excitability in fragile X syndrome. Front Synaptic Neurosci 2:10
Mizrahi A, Katz LC (2003) Dendritic stability in the adult olfactory bulb. Nat Neurosci
6:1201–1207
Morris RG, Hagan JJ, Rawlins JN (1986) Allocentric spatial learning by hippocampectomised rats:
a further test of the “spatial mapping” and “working memory” theories of hippocampal function.
Q J Exp Psychol B 38:365–395
Murphy DD, Cole NB, Greenberger V, Segal M (1998) Estradiol increases dendritic spine
density by reducing GABA neurotransmission in hippocampal neurons. J Neurosci
18:2550–2559
Nägerl UV, Eberhorn N, Cambridge SB, Bonhoeffer T (2004) Bidirectional activity-dependent
morphological plasticity in hippocampal neurons. Neuron 44:759–767
Nevian T, Sakmann B (2004) Single spine Ca2+ signals evoked by coincident EPSPs and
backpropagating action potentials in spiny stellate cells of layer 4 in the juvenile rat somato-
sensory barrel cortex. J Neurosci 24:1689–1699
Nicoll RA, Malenka RC (1995) Contrasting properties of two forms of long-term potentiation in the
hippocampus. Nature 377:115–118
Nicoll RA, Schmitz D (2005) Synaptic plasticity at hippocampal mossy fiber synapses. Nat Rev
Neurosci 6:863–876
Niell CM, Smith SJ (2004) Live optical imaging of nervous system development. Annu Rev
Physiol 66:771–798
Niell CM, Meyer MP, Smith SJ (2004) In vivo imaging of synapse formation on a growing dendritic
arbor. Nat Neurosci 7:254–260
Nimchinsky EA, Sabatini BL, Svoboda K (2002) Structure and function of dendritic spines. Annu
Rev Physiol 64:313–354
Nowak L, Bregestovski P, Ascher P, Herbet A, Prochiantz A (1984) Magnesium gates glutamate-
activated channels in mouse central neurones. Nature 307:462–465
Nusser Z (2000) AMPA and NMDA receptors: similarities and differences in their synaptic
distribution. Curr Opin Neurobiol 10:337–341
O’Malley A, O’Connell C, Murphy KJ, Regan CM (2000) Transient spine density increases in the
mid-molecular layer of hippocampal dentate gyrus accompany consolidation of a spatial
learning task in the rodent. Neuroscience 99:229–232
Okamoto K, Nagai T, Miyawaki A, Hayashi Y (2004) Rapid and persistent modulation of actin
dynamics regulates postsynaptic reorganization underlying bidirectional plasticity. Nat Neurosci
7:1104–1112
Olmos G, Naftolin F, Perez J, Tranque PA, Garcia-Segura LM (1989) Synaptic remodeling in the rat
arcuate nucleus during the estrous cycle. Neuroscience 32:663–667
Oray S, Majewska A, Sur M (2004) Dendritic spine dynamics are regulated by monocular
deprivation and extracellular matrix degradation. Neuron 44:1021–1030
Ostroff LE, Fiala JC, Allwardt B, Harris KM (2002) Polyribosomes redistribute from dendritic
shafts into spines with enlarged synapses during LTP in developing rat hippocampal slices.
Neuron 35:535–545
Overly CC, Rieff HI, Hollenbeck PJ (1996) Organelle motility and metabolism in axons vs
dendrites of cultured hippocampal neurons. J Cell Sci 109:971–980
Pacelli GJ, Su W, Kelso SR (1989) Activity-induced depression of synaptic inhibition during
LTP-inducing patterned stimulation. Brain Res 486:26–32
Pare D, Shink E, Gaudreau H, Destexhe A, Lang EJ (1998) Impact of spontaneous synaptic activity
on the resting properties of cat neocortical pyramidal neurons in vivo. J Neurophysiol
79:1450–1460
Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM (2011) Dendritic spine pathology
in neuropsychiatric disorders. Nat Neurosci 14:285–293
Peters A, Kaiserman-Abramof IR (1970) The small pyramidal neuron of the rat cerebral cortex. The
perikaryon, dendrites and spines. Am J Anat 127:321–355
Peters A, Palay SL, Webster H, De F (1991) The fine structure of the nervous system. Oxford
University Press, New York
Pfeiffer BE, Huber KM (2007) Fragile X mental retardation protein induces synapse loss through
acute postsynaptic translational regulation. J Neurosci 27:3120–3130
Polsky A, Mel BW, Schiller J (2004) Computational subunits in thin dendrites of pyramidal cells.
Nat Neurosci 7:621–627
Portera-Cailliau C, Pan DT, Yuste R (2003) Activity-regulated dynamic behavior of early dendritic
protrusions: evidence for different types of dendritic filopodia. J Neurosci 23:7129–7142
Prieto JJ, Winer JA (1999) Layer VI in cat primary auditory cortex: Golgi study and sublaminar
origins of projection neurons. J Comp Neurol 404:332–358
Raastad M, Enriquez-Denton M, Kiehn O (1998) Synaptic signaling in an active central network
only moderately changes passive membrane properties. Proc Natl Acad Sci U S A
95:10251–10256
Ramón y Cajal S (1995) Histology of the nervous system of man and vertebrates (trans: Swanson N,
Swanson LW). Oxford University Press, New York (originally published: Histology du système
nerveux de l’homme et des vèrtebrès (trans: Azoulay L). Paris, pp 1909–1911
Ribak CE, Tran PH, Spigelman I, Okazaki MM, Nadler JV (2000) Status epilepticus-induced hilar
basal dendrites on rodent granule cells contribute to recurrent excitatory circuitry. J Comp
Neurol 428:240–253
Rollenhagen A, Sätzler K, Rodriguez EP, Jonas P, Frotscher M, L€ ubke JHR (2007) Structural
determinants of transmission at large hippocampal mossy fiber synapses. J Neurosci
27:10434–10444
Rudick CN, Woolley CS (2001) Estrogen regulates functional inhibition of hippocampal CA1
pyramidal cells in the adult female rat. J Neurosci 21:6532–6543
Rudick CN, Woolley CS (2003) Selective estrogen receptor modulators regulate phasic activation
of hippocampal CA1 pyramidal cells by estrogen. Endocrinology 144:179–187
Ruigrok TJ, de Zeeuw CI, van der Burg J, Voogd J (1990) Intracellular labeling of neurons in the
medial accessory olive of the cat: I. Physiology and light microscopy. J Comp Neurol
300:462–477
Salin PA, Scanziani M, Malenka RC, Nicoll RA (1996) Distinct short-term plasticity at two
excitatory synapses in the hippocampus. Proc Natl Acad Sci U S A 93:13304–13309
Scheff SW, Price DA (2003) Synaptic pathology in Alzheimer’s disease: a review of ultrastructural
studies. Neurobiol Aging 24:1029–1046
Schiller J, Schiller Y, Clapham DE (1998) NMDA receptors amplify calcium influx into dendritic
spines during associative pre- and postsynaptic activation. Nat Neurosci 1:114–118
ubke
Segal M, Vlachos A, Korkotian E (2010) The spine apparatus, synaptopodin, and dendritic spine
plasticity. Neuroscientist 16:125–131
Selig DK, Lee HK, Bear MF, Malenka RC (1995) Reexamination of the effects of MCPG on
hippocampal LTP, LTD, and depotentiation. J Neurophysiol 74:1075–1082
Sholl DA (1956) The measurable parameters of the cerebral cortex and their significance in its
organization. Prog Neurobiol 2:324–333
Sjöström PJ, Häusser M (2006) A cooperative switch determines the sign of synaptic plasticity in
distal dendrites of neocortical pyramidal neurons. Neuron 51:227–238
Somogyi P, Klausberger T (2005) Defined types of cortical interneurone structure space and spike
timing in the hippocampus. J Physiol 562:9–26
Sorra KE, Harris KM (1998) Stability in synapse number and size at 2 hr after long-term
potentiation in hippocampal area CA1. J Neurosci 18:658–671
Spacek J (1985) Three-dimensional analysis of dendritic spines. II. Spine apparatus and other
cytoplasmic components. Anat Embryol 171:235–243
Spacek J, Harris KM (1997) Three-dimensional organization of smooth endoplasmic reticulum in
hippocampal CA1 dendrites and dendritic spines of the immature and mature rat. J Neurosci
17:190–203
Spruston N, Schiller Y, Stuart G, Sakmann B (1995a) Activity-dependent action potential invasion
and calcium influx into hippocampal CA1 dendrites. Science 268:297–300
Spruston N, Jonas P, Sakmann B (1995b) Dendritic glutamate receptor channels in rat hippocampal
CA3 and CA1 pyramidal neurons. J Physiol 482:325–352
Stevens CF (1998) A million dollar question: does LTP = memory? Neuron 20:1–2
Steward O, Reeves TM (1988) Protein-synthetic machinery beneath postsynaptic sites on CNS
neurons: association between polyribosomes and other organelles at the synaptic site. J Neurosci
8:176–184
Stuart GJ, Häusser M (2001) Dendritic coincidence detection of EPSPs and action potentials. Nat
Neurosci 4:63–71
Stuart G, Spruston N, Sakmann B, Häusser M (1997a) Action potential initiation and
backpropagation in neurons of the mammalian CNS. Trends Neurosci 20:125–131
Stuart G, Schiller J, Sakmann B (1997b) Action potential initiation and propagation in rat neocor-
tical pyramidal neurons. J Physiol 505:617–632
Stuart G, Spruston N, Häusser M (2008) Dendrites, 2nd edn. Oxford University Press, New York
Svoboda K, Tank DW, Denk W (1996) Direct measurement of coupling between dendritic spines
and shafts. Science 272:716–719
Takumi Y, Matsubara A, Rinvik E, Ottersen OP (1999) The arrangement of glutamate receptors in
excitatory synapses. Ann N Y Acad Sci 868:474–482
Toni N, Buchs PA, Nikonenko I, Bron CR, Muller D (1999) LTP promotes formation of multiple
spine synapses between a single axon terminal and a dendrite. Nature 402:421–425
Tóth K, Suares G, Lawrence JJ, Philips-Tansey E, McBain CJ (2000) Differential mechanisms of
transmission at three types of mossy fiber synapse. J Neurosci 20:8279–8289
Trachtenberg JT, Chen BE, Knott GW, Feng G, Sanes JR, Welker E, Svoboda K (2002) Long-term
in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature
420:788–794
Trimmer JS, Rhodes KJ (2004) Localization of voltage-gated ion channels in mammalian brain.
Annu Rev Physiol 66:477–519
Trommald M, Hulleberg G (1997) Dimensions and density of dendritic spines from rat dentate
granule cells based on reconstructions from serial electron micrographs. J Comp Neurol
377:15–28
Trommald M, Hulleberg G, Andersen P (1996) Long-term potentiation is associated with new
excitatory spine synapses on rat dentate granule cells. Learn Mem 3:218–228
Tsubokawa H, Ross WN (1996) IPSPs modulate spike backpropagation and associated [Ca2+]i
changes in the dendrites of hippocampal CA1 pyramidal neurons. J Neurophysiol
76:2896–2906
Turrigiano GG, Nelson SB (1998) Thinking globally, acting locally: AMPA receptor turnover and
synaptic strength. Neuron 21:933–935
Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB (1998) Activity-dependent scaling
of quantal amplitude in neocortical neurons. Nature 391:892–896
Umeda T, Ebihara T, Okabe S (2005) Simultaneous observation of stably associated presynaptic
varicosities and postsynaptic spines: morphological alterations of CA3-CA1 synapses in hip-
pocampal slice cultures. Mol Cell Neurosci 28:264–274
Uylings HB, Kuypers K, Diamond MC, Veltman WA (1978) Effects of differential environments on
plasticity of dendrites of cortical pyramidal neurons in adult rats. Exp Neurol 62:658–677
Valverde F (1967) Apical dendritic spines of the visual cortex and light deprivation in the mouse.
Exp Brain Res 3:337–352
Van Harreveld A, Fifková E (1975) Swelling of dendritic spines in the fascia dentata after
stimulation of the perforant fibers as a mechanism of post-tetanic potentiation. Exp Neurol
49:736–749
Van Spronsen M, Hoogenraad CC (2010) Synapse pathology in psychiatric and neurologic disease.
Curr Neurol Neurosci Rep 10:207–214
Ventura R, Harris KM (1999) Three-dimensional relationships between hippocampal synapses and
astrocytes. J Neurosci 19:6897–6906
Wallace W, Bear MF (2004) A morphological correlate of synaptic scaling in visual cortex.
J Neurosci 24:6928–6938
Witkin JW, Ferin M, Popilskis SJ, Silverman AJ (1991) Effects of gonadal steroids on the
ultrastructure of GnRH neurons in the rhesus monkey: synaptic input and glial apposition.
Endocrinology 129:1083–1092
Wolf S (2011) Erzeugung von hippocampalen Neuronen und Netzwerken der CA1-Region
innerhalb des Softwaretools NeuGen. Master thesis, Ruperto-Carola-University Heidelberg
Wolf S, Queisser G (submitted) Employing NeuGen 2.0 to automatically generate realistic mor-
phologies of hippocampal neurons and neural networks in 3D
Woolley CS, Cohen RS (2002) Sex steroids and neuronal growth in adulthood. In: Pfaff DW,
Arnold A, Etgen A, Fahrbach S, Rubin R (eds) Hormones, brain and behavior, vol 4. Academic,
San Diego, pp 717–777
Woolley CS, McEwen BS (1993) Roles of estradiol and progesterone in regulation of hippocampal
dendritic spine density during the estrous cycle in the rat. J Comp Neurol 336:293–306
Woolley CS, Wenzel HJ, Schwartzkroin PA (1996) Estradiol increases the frequency of multiple
synapse boutons in the hippocampal CA1 region of the adult female rat. J Comp Neurol
373:108–117
Xu-Friedman MA, Regehr WG (2003) Ultrastructural contributions to desensitization at cerebellar
mossy fiber to granule cell synapses. J Neurosci 23:2182–2192
Xu-Friedman MA, Harris KM, Regehr WG (2001) Three-dimensional comparison of ultrastructural
characteristics at depressing and facilitating synapses onto cerebellar Purkinje cells. J Neurosci
21:6666–6672
Yankova M, Hart SA, Woolley CS (2001) Estrogen increases synaptic connectivity between single
presynaptic inputs and multiple postsynaptic CA1 pyramidal cells: a serial electron-microscopic
study. Proc Natl Acad Sci U S A 98:3525–3530
Yuste R, Majewska A, Cash SS, Denk W (1999) Mechanisms of calcium influx into hippocampal
spines: heterogeneity among spines, coincidence detection by NMDA receptors, and optical
quantal analysis. J Neurosci 19:1976–1987
Yuste R (2010) Dendritic spines. MIT Press, Cambridge. ISBN 978-0-262-01350-5
Yuste R, Majewska A, Holthoff K (2000) From form to function: calcium compartmentalization in
dendritic spines. Nat Neurosci 3:653–659
Zhang LI, Tao HW, Holt CE, Harris WA, Poo M (1998) A critical window for cooperation and
competition among developing retinotectal synapses. Nature 395:37–44
Zhou Q, Homma KJ, Poo MM (2004) Shrinkage of dendritic spines associated with long-term
depression of hippocampal synapses. Neuron 44:749–757
ubke
Zito K, Knott G, Shepherd GM, Shenolikar S, Svoboda K (2004) Induction of spine growth and
synapse formation by regulation of the spine actin cytoskeleton. Neuron 44:321–334
Ziv NE, Smith SJ (1996) Evidence for a role of dendritic filopodia in synaptogenesis and spine
formation. Neuron 17:91–102
Zukin RS, Bennett MV (1995) Alternatively spliced isoforms of the NMDARI receptor subunit.
Trends Neurosci 18:306–313

Rollenhagen-Lübke2016 ReferenceWorkEntry DendriticElaborationMorphology

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Rollenhagen-Lübke2016 ReferenceWorkEntry DendriticElaborationMorphology

Uploaded by

Copyright:

Available Formats

Dendritic Elaboration: Morphology and

# Springer Science+Business Media New York 2016 225

integrate and process thousands of excitatory, and to a lesser extent inhibitory,

potentials (EPSPs) • Filopodia • Hormone induced structural dendritic plasticity •

Finally, phylogenetic differences in speciﬁc neuronal morphologies further sup-

Dendritic Arborization Patterns

Subcellular Structure of Dendrites

Dendritic Specializations and Appendages

Fine Structure of Dendritic Spines

The large variability of spine geometries is accompanied also by a huge diversity in

to facilitate rapid calcium-induced changes in their shape (Fifková 1985a, b; Fischer

The NMDA receptor is sensitive to neurotransmitter release and membrane depo-

EPSP potentiation S1 (%)

EPSP potentiation S2 (%)

long-lasting activity-dependent synaptic enhancement was found in many brain

Properties of the NMDA Receptor

Dendritic Integration and Its Role in Synaptic Plasticity

Spike-timing-dependent plasticity (STDP) is a special type of synaptic potentiation

EPSP amplitude (% of control)

Dendritic Excitability and Synaptic Plasticity

Dendrites like axons contain voltage-gated Na+ (Nav1.1–Nav1.12) channels out of

fashion. Their cell surface distribution seems to be as complex and as highly

Actin polymerization (red: polymerized; blue: depolymerized)

Subsequent in vivo imaging through a thinned skull or a cranial window over

Experience Induced Structural Dendritic Plasticity

Dendritic structures, in particular dendritic spines, undergo severe alterations with

Sensory Deprivation, Enriched Environment and Behavioral Training

Other methods have been used to study experience-induced changes in dendritic

particular on terminal basal dendrites (Uylings et al. 1978) or differences in synapse

Hormone Induced Structural Dendritic Plasticity

It is now well established that hormones, in particular estrogen is a powerful

Abnormalities in dendritic structural plasticity are a characteristic feature of many

synaptic input. This led to profound reduction, deformation and disorientation of

Markram H, L€ ubke J, Frotscher M, Sakmann B (1997) Regulation of synaptic efﬁcacy by coinci-

You might also like