Cell and Tissue Research

https://doi.org/10.1007/s00441-017-2782-x

REVIEW

BDNF effects on dendritic spine morphology and hippocampal function

Oliver von Bohlen und Halbach 1 & Viola von Bohlen und Halbach 1

Received: 12 September 2017 / Accepted: 22 December 2017

# Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract
Neurotrophins, including brain-derived neurotrophic factor (BDNF), are expressed in the hippocampus, as well as their precur-
sors, the pro-neurotrophins. The neurotrophins signal through specific tyrosine kinase receptors and the low affinity receptor
p75NTR. Moreover, the pro-neurotrophins are considered to be biologically active by signaling through specific receptors. The
neurotrophins, especially BDNF, are involved in processes related to learning and memory. Furthermore, it is thought that BDNF
also plays a crucial role in major depression. This points to a role of BDNF as a central regulator of neuronal plasticity within the
postnatal hippocampus. Morphological correlates of neuronal plasticity are changes on the level of the dendritic spines and, at
least in the dentate gyrus of the hippocampus, on the level of adult neurogenesis. Specific changes in dendritic spines as well as in
adult hippocampal neurogenesis can be seen in the context of several forms of learning and memory, and it is known that
depression is accompanied by declines in the rate of adult neurogenesis and in spine densities. The possible roles of BDNF in
neuronal plasticity within the hippocampus are highlighted in this review by focusing on the morphological components of
neuronal plasticity.

Keywords Enriched environment . Voluntary exercise . p75NTR . trkB . Dendritic spine

The hippocampal formation
The hippocampal formation is composed of the cornu
ammonis (areas CA1–CA3), the dentate gyrus (DG) and the
subicular complex (Squire and Zola 1996). The hippocampus
has a three-laminar composition. Areas CA1–CA3 are com-
posed of: (1) the stratum oriens, (2) the stratum pyramidale
(which consist of cell bodies of the pyramidal neurons), and
(3) the stratum radiatum/lacunosum moleculare. The bound-
aries of areas CA1–CA3 are not easy to define in standard
stained sections. Using immunohistochemistry, the bound-
aries can be exactly defined by using PCP-4 as a specific
marker for CA2 neurons (Renelt et al. 2014).
The DG also has a laminar organization [stratum
moleculare, stratum granulosum (which consists of the cell
bodies of the granule cells) and stratum multiforme]. A sub-
structure belonging to the DG is the subgranular zone. This
* Oliver von Bohlen und Halbach
oliver.vonbohlen@uni-greifswald.de
1
Institut für Anatomie und Zellbiologie, Universitätsmedizin
Greifswald, Friedrich-Loeffler-Str. 23c, 17487 Greifswald, Germany
small cell layer is located at the basis of the stratum
granulosum and cells located in this substructure are capable
of adult neurogenesis (see below). Different parts of the hip-
pocampus (DG, CA3, CA1) are interconnected by the so-
called tri-synaptic circuit (Hasselmo and McClelland 1999;
Naber et al. 2000), which plays a fundamental role in mecha-
nisms attributed to hippocampal learning and memory forma-
tion. The hippocampal formation is, e.g., implicated in episod-
ic and spatial memory (Rolls 2000). Moreover, memory for a
new experience is thought to depend on information stored in
both the hippocampus and neocortex (Squire et al. 2015), and
consolidation is thought to represent a process by which the
hippocampus guides the reorganization of the information
stored in the neocortex such that it can become independent
of the hippocampus (Squire et al. 2015). Thus, the newly
acquired hippocampal information is transferred to the neo-
cortex and stored as a long-lasting memory trace (Mizuseki
and Miyawaki 2017). Since the hippocampus is capable of
storing information for a certain time, plastic changes are re-
quired that allow a reorganization of hippocampal structures
for several hours or even longer. These changes occurring on
the synaptic level within the hippocampus have been shown
for the first time in the early 1970s (Bliss and Collingridge
1993; Bliss and Lomo 1973). This long-term potentiation

(LTP) requires, among others, a long-lasting increase in the
efficiency of synaptic transmission. This increase in the effi-
ciency of synaptic transmission can lead to structural changes
in individual neurons that result in a rearrangement of the
hippocampal network. Plastic rearrangement of connectivities
within the hippocampus can be seen not only on the cellular
level but also on the sub-cellular level. The sub-cellular struc-
tures that play a pivotal role in these processes are the so-
called dendritic spines. These structures can be altered under
various physiological and pathophysiological conditions.
Correlates of neuronal plasticity
Dendritic spines
The most prominent cells that determine the morphology of
the hippocampus are the pyramidal neurons that form the py-
ramidal layers of areas CA1–CA3 and the granule cells locat-
ed in the upper and lower leaves of the DG. A morphological
correlate of neuronal plasticity is represented by the density
and morphology of the dendritic spines, which are the main
sites of synaptic input for neurons. Neurotransmitter receptors
are largely restricted to the surface of dendritic spines and
concentrate close to the presynaptic element. A single pyra-
midal cell in area CA1, for example, receives about 3000
excitatory and 1700 inhibitory inputs (Megias et al. 2001),
and the distal dendrites in the stratum radiatum and stratum
oriens, which form about 68.5% of the dendritic trees of the
CA1 pyramidal cells, are densely packed with dendritic spines
and the excitatory inputs terminate exclusively on them
(Megias et al. 2001). A dendritic spine is composed of a nar-
row neck and a head and individual dendritic spines can dis-
play great morphological diversities. Thus, a dendritic spine
can change its shape within a short time from a dendritic spine
with a large head and a narrow neck (a so-called Bmushroom
spine^) to a so-called Bthin spine^ with a smaller head and a
narrow neck (Parnass et al. 2000; von Bohlen und Halbach
2010a).
Dendritic spines are formed postnatally. A dramatic in-
crease in the densities of dendritic spines can, for example,
be observed from postnatal day 1 (P1) to postnatal day 12
(P12) in the hippocampal field CA1 of rats (Fiala et al.
1998). Moreover, from P15 to adulthood, the number of den-
dritic spines in the CA1 hippocampal field of rats nearly dou-
bles (Harris et al. 1992). Exposure of animals to an enriched
environment improves the performance in several learning
tasks and increases the rate of adult hippocampal neurogenesis
(Bruel-Jungerman et al. 2005). Furthermore, an enriched en-
vironment has been found to increase dendritic spine density
in the hippocampus of rodents (Altschuler 1979). Since an
enriched environment has an impact on neuronal plasticity
as well as on learning performance (Rampon et al. 2000),
Cell Tissue Res
changes in the number or shape of dendritic spines could
represent a morphological correlate of neuronal plasticity,
learning and memory. Indeed, several forms of learning have
been shown to increase the number of dendritic spines
(Geinisman 2000; Leuner et al. 2003; Nimchinsky et al.
2002; Yuste and Bonhoeffer 2001). For example, it has been
demonstrated that spatial learning is associated with an in-
crease in hippocampal spine densities (Moser et al. 1994),
whereas a decline in hippocampal spines densities and defi-
ciencies in spatial memory can be observed in aged mice (von
Bohlen und Halbach et al. 2006a).
Adult hippocampal neurogenesis
A further morphological correlate of neuronal hippocampal
plasticity is seen in the DG. The DG is one of the brain regions
capable of generating new neurons postnatally. This process,
termed adult neurogenesis, occurs constitutively throughout
postnatal life in the DG, whereby the rate of adult
neurogenesis can be altered under various physiological and
pathophysiological conditions. Adult neurogenesis within the
DG can, e.g., be influenced by the environment and behaviour
(Eriksson et al. 1998; Kempermann et al. 1997; van Praag
et al. 1999), and the adult-born neurons are thought to con-
tribute to learning and memory (Goncalves et al. 2016).
Somewhat comparable to changes occurring in the densities
or shape of dendritic spines, several hippocampal-dependent
learning tasks, as well as an enriched environment, can in-
crease the rate of hippocampal neurogenesis (Bruel-
Jungerman et al. 2005; van Praag et al. 1999). Thus, on the
morphological level, neuronal plasticity is reflected by chang-
es in dendritic spines and, concerning the DG, also by the
addition of new and functional neurons (Fig. 1).
Long-term potentiation and long-term depression
LTP was observed for the first time in 1966 (Lømo 2018). LTP
is an activity-induced long-lasting increase in excitatory syn-
aptic strength that is thought to represent a cellular correlate of
learning and memory (Bliss and Collingridge 1993; Bliss and
Lomo 1973; Malenka and Nicoll 1999). However, for a long
period of intensive research, it has never been shown that
learning actually induces LTP in the hippocampal field CA1.
Finally, in 2006, Whitlock and co-workers were able to dem-
onstrate that learning in a memory task induces LTP-like syn-
aptic plasticity in the hippocampal area CA1 (Whitlock et al.
2006). Furthermore, it has been shown that LTP seems to be
associated with increased spine densities (Muller et al. 2000),
and with the formation of new, mature and probably function-
al synapses (Toni et al. 1999).
Long-term depression (LTD) is thought to play an integral
role in the processing and retention of information, but, in
contrast to LTP, LTD is a long-lasting reduction in synaptic
Cell Tissue Res
Fig. 1 Morphological correlates of neuronal plasticity include changes in
the densities or shape of dendrites or changes in the rate of adult
neurogenesis. a Example of Golgi-impregnated neurons in the granular
layer of the dentate gyrus. The displayed image is a z-projection of a z-
stack (39 single images, z-spacing: 0.25 μm). The soma and the main
dendrites are clearly visible at that magnification, but dendritic spines are
hard to detect. b Example of Golgi-impregnated dendrites in the molec-
ular layer of the dentate gyrus in a higher magnification (using a ×100 oil
objective). The displayed image is a z-projection of a z-stack (53 single
images, z-spacing: 0.125 μm). In this view, the depth of the section is not
transmission that results from low-frequency stimulation
(Pinar et al. 2017). LTD can induce a loss of dendritic spines
(Hasegawa et al. 2015). It is suggested that LTD-induced sig-
naling pathways related to apoptosis play a crucial role in the
weakening and elimination of synapses and dendritic spines
(Sheng and Erturk 2014). However, LTD is not only associat-
ed with declines in spine densities but also with zshrinkage of
hippocampal dendritic spines (Monfils and Teskey 2004;
Zhou et al. 2004). This shrinkage has been assumed to con-
tribute to activity-dependent elimination of synaptic connec-
tions (Zhou et al. 2004). Thus, dendritic spines can undergo
distinct morphological changes in response to different forms
of neuronal activity.
It has been shown that LTP increases (Engert and
Bonhoeffer 1999) and LTD decreases (Monfils and Teskey
2004) spine densities, and that LTD also causes morphological
changes of presynaptic boutons leading to a reduction in their
contacts with spines (Becker et al. 2008). This may argue for a
visible. In zcase of a reconstruction using such combined images, the
spine densities will be over-estimated. c Example of newly formed neu-
rons in the dentate gyrus. These newly formed neurons can be visualized
with antibodies directed against doublecortin (shown in red; DAPI (in
blue) was used to visualize cell nuclei). The newly formed neurons extend
their dendrites towards the molecular layer, but these neurons are not
mature and dendritic spines are hardly visible (21 single images per chan-
nel; z-spacing: 0.35 μm; deconvolution: maximum likelihood estimation;
EFI projection)
strong association between synaptic transmission and alter-
ations in dendritic spines, and indicates that LTP- or LTD-
induced activity can induce long-lasting changes in the hippo-
campal synaptic networks. The changes in the number and
morphology of dendritic spines in the hippocampal areas
CA1–CA3 as well as in the DG represents a morphological
correlate of neuronal plasticity in the hippocampus.
Interestingly, changes in neuronal plasticity on the morpho-
logical as well as on the physiological level can be influenced
by the presence or absence of trophic factors such as, for
example, by members of the family of neurotrophins.
The family of neurotrophins
Brain-derived neurotrophic factor (BDNF) as well as nerve
growth factor (NGF), neurotrophin-3 (NT-3) and
neurotrophin-4 (NT-4) belong to the family of neurotrophins.

The mature neurotrophins bind to specific receptors that be-
long to the class of the trk family of tyrosine protein kinase
receptors (trkA, trkB, trkC). NGF mainly signals through trkA
receptors, while BDNF, as well as NT-4, specifically activate
trkB receptors, and NT-3 primarily activates the trkC recep-
tors. In addition, all neurotrophins can signal through a low-
affinity receptor (which is structurally unrelated to the trk re-
ceptors), the so-called p75 neurotrophin receptor, or p75NTR
(Barbacid 1994; Barker 1998).
The four members of the neurotrophin family are initially
synthesized as precursors or pro-neurotrophins containing at
their N-termini signal peptides followed by the pro-region.
The pro-neurotrophins undergo proteolytic cleavage to yield
mature neurotrophins, which dimerize after translation
(Kolbeck et al. 1994). It has been long believed that only the
mature neurotrophins exert biological functions by acting
through their specific receptors. Interestingly, different roles
for the pro-neurotrophins in developmental and injury-
induced cell death, as well as in synaptic plasticity, have also
been shown.
Pro-neurotrophins, including the precursor of BDNF (pro-
BDNF), may be secreted from cells or cleaved intracellularly
by furin or pro-convertases to yield C-terminal mature
neurotrophin dimers (Foltran and Diaz 2016). Pro-BDNF
seems not only to represent a precursor for the biologically
active BDNF but also to represent a biologically active sub-
stance of its own. It is thought that pro-BDNF is apparently
the main form secreted in vivo and that the regulated equilib-
rium between pro-BDNF and mature BDNF is decisive for
physiological as well as pathological conditions (Foltran and
Diaz 2016). One role of tissue plasminogen activator (tPA), a
serine protease, is its involvement in the cleavage of pro-
BDNF to BDNF. A hippocampus-specific deletion of tPA in
adult mice ameliorates depression and anxiety-like behaviour
(Bahi and Dreyer 2012), which may indeed argue for a bal-
anced expression of pro-BDNF and mature BDNF.
Currently, it is thought that mature BDNF is capable of
mainly activating trkB receptors but that all mature
neurotrophins, including BDNF, can also activate the low-
affinity receptor p75NTR. Pro-BDNF seems not to activate
trkB receptors, but is thought to signal through p75NTR and
a specific co-receptor, sortilin (Teng et al. 2005). These recep-
tors are not only expressed in the developing brain but also in
the adult brain, whereby these receptors are differentially
expressed in the adult hippocampus.
The mature neurotrophins not only play important roles in
the context of neuronal survival but they have also been
shown to play important roles in the maintenance of the archi-
tecture of the adult brain. Moreover, neurotrophins, especially
BDNF, have important roles in neuronal plasticity and in
physiological and morphological processes related to learning
and memory. Compared to other organs, like liver or spleen,
high BDNF levels can be detected in the brain (Katoh-Semba
Cell Tissue Res
et al. 1997). High BDNF levels in the postnatal brain have
been found, e.g., within the olfactory bulb, cerebral cortex,
septum, hypothalamus, striatum, cerebellum and, especially,
in the hippocampus (Katoh-Semba et al. 1997). Using primary
murine hippocampal cultures, it has been shown that BDNF
levels increased stepwise from embryonic day 15 until the
second postnatal week, whereas trkB expression was stable
throughout development. Moreover, neurons and astrocytes
expressed both BDNF and trkB (Ivanova and Beyer 2001).
Interestingly, in humans, the levels of BDNF mRNA did not
change significantly in the hippocampus with age (Webster
et al. 2006).
Lack of functional NGF, BDNF and NT3 genes results in
severe neuronal deficits and in early postnatal death (Conover
and Yancopoulos 1997). Mice lacking BDNF mainly die dur-
ing the second postnatal week and only some survive into
adulthood (Ernfors et al. 1994). However, heterozygous
BDNF knockout mice survive into adulthood and can be an-
alyzed. The heterozygous BDNF knockout mice display in-
creased locomotor activity and a strong increase in body
weight (Kernie et al. 2000). Another approach for investigat-
ing the effects of a deletion of BDNF in the central nervous
system is the use of conditional knockout mice. Concerning
the analysis of BDNF functions in the postnatal hippocampus,
calcium-calmodulin-dependent protein kinase II (CaMKII)-
Cre transgenic mice or GFAP-Cre transgenic mice might be
of specific interest. Such conditional BDNF mouse lines have
been created, e.g., by Monteggia et al. (2007). In the hippo-
campus, GFAP conditional BDNF knockout mice showed an
almost complete ablation of BDNF mRNA expression, while
the CaMKII conditional knockout mice displayed a less com-
plete reduction in BDNF in these regions (Monteggia et al.
2007). Both male GFAP-Cre, as well as CaMKII-Cre condi-
tional BDNF knockout mice, exhibited significantly increased
locomotor activity as compared to control littermates
(Monteggia et al. 2007).
As mentioned above, pro-BDNF is enzymatically cleaved
to generate mature BDNF and its pro-peptide. Interestingly,
not only do BDNF and pro-BDNF have biological activity but
also the pro-peptide. Both BDNF and its pro-peptide have
been found to be stored in presynaptic dense core vesicles in
hippocampal neurons (Dieni et al. 2012), and BDNF pro-
peptide also seems to be involved in neuronal plasticity
(Mizui et al. 2017).
Receptors for BDNF and pro-BDNF
TrkB receptors
The trkB tyrosine kinase receptor shows strong binding pref-
erences for BDNF and is expressed in the hippocampus by
both neurons and astrocytes (Ivanova and Beyer 2001).
Cell Tissue Res
Within the hippocampus, trkB is widely and strongly
expressed in the granule layer of the DG, in the stratum
pyramidale of areas CA1–CA3 and within the subiculum
(Yan et al. 1997), and in moderate levels in the stratum
radiatum, stratum lacunosum moleculare and the molecular
layer of the DG (Yan et al. 1997). In humans, however, (and in
contrast to BDNF), the levels of trkB mRNA in the hippocam-
pus decrease with age (Webster et al. 2006). Binding of BDNF
to the trkB receptor induces ligand–receptor dimerization and
autophosphorylation of tyrosine residues. Three main intracel-
lular signaling cascades are activated by the trkB receptor
(Minichiello 2009):
the Ras–mitogen-activated protein kinase (MAPK)
pathway,
the phosphatidylinositol 3 kinase (PI3K)–Akt pathway
and
the PLCgamma–Ca2+ pathway.
For gaining insight intp the roles of trkB, mice have been
generated that carry a germline mutation in the tyrosine kinase
catalytic domain of the trkB gene. The mice, homozygous for
this mutation, develop to birth, but die shortly after birth
(Klein et al. 1993). Interestingly, during early postnatal life,
the homozygous trkB knockout mice display a significant
increase in apoptotic cell death in different regions of the
brain, including the hippocampus (Alcantara et al. 1997).
Comparable to BDNF knockout mice, the heterozygous trkB
knockout mice survive into adulthood, and even aged hetero-
zygous mice (about 2 years of age) can be analyzed (von
Bohlen und Halbach et al. 2003). However, to analyze the
effect of a complete deletion of trkB in the central nervous
system conditional trkB knockout mice would be helpful.
Indeed, different conditional trkB knockout mouse lines have
been generated, such as, e.g., CaMKII-Cre transgenic mice
(Minichiello et al. 1999), mice with a targeted mutation in
the Shc- and PLCgamma-docking sites of trkB (Medina et al.
2004), or mice with a conditional ablation of the trkB in
parvalbumin-expressing interneurons (Xenos et al. 2017;
Zheng et al. 2011).
P75 neurotrophin receptor (p75NTR)
Within the postnatal forebrain, the strongest expression of
p75NTR is found in brain areas containing the cholinergic
projection neurons (such as in the septum, the diagonal band
and the basal nucleus of Meynert) or cholinergic
interneurones, such as, e.g., in the caudate putamen
(Maclean et al. 1997).
In young mice (postnatal day 21), high levels of p75NTR
mRNA can be found to be expressed by granule cells of the
DG and by pyramidal neurons of areas CA1–CA3
(Zagrebelsky et al. 2005). By using standard
immunohistochemistry, p75NTR-positive cells within the
adult hippocampus were at first not detected (Lee et al.
1998). By using light microscopy as well as electron micros-
copy, it has been demonstrated that p75NTR can be found
within the hippocampal formation. Within the DG, p75NTR
is mainly localized presynaptically, but also can be found in
astrocytes and in the dendrites and somata of some granule
cells (Dougherty and Milner 1999). Moreover, by using elec-
tron microscopy, p75NTR has been shown to localize in den-
dritic spines, in addition to afferent terminals, of CA1 neurons
(Woo et al. 2005). Along this line, another group has demon-
strated the presence of p75NTR immunoreactivity in neuronal
cell bodies in the stratum oriens and within the DG (Barrett
et al. 2005).
In general, the physiological roles of p75NTR are complex,
and p75NTR not only interacts with trk receptors (Barker
1998) but also with sortilin (see below). It is thought that the
mature neurotrophins can signal via trk and p75NTR. In ad-
dition to mature neurotrophins, pro-neurotrophins, like pro-
BDNF, can be secreted and bind to the p75NTR–sortilin com-
plex (Lee et al. 2001; Teng et al. 2005). However, the signal-
ing mechanisms of p75NTR are even more complex and can
therefore contribute to a variety of biological actions.
P75NTR, among others, can also interact with NogoR,
Lingo-1, Neurophilin-1 or Ephrin-A (see, for a detailed
review Teng et al. 2010). Moreover, the p75 neurotrophin
receptor exists in least in two isoforms: a short (s-p75NTR)
and a full-length isoform. The full-length isoform is capable of
binding neurotrophins, whereas the short isoform lacks the
neurotrophin binding site. Although the functions of s-
p75NTR are largely unknown, some studies suggest that it is
a functional receptor in vivo (Fujii and Kunugi 2009).
In humans, the p75NTR gene maps to chromosome 17q21-
q22 and consistd of six exons and five introns (Kunugi et al.
2004). It has been shown that a missense polymorphism
(S205 L) in the p75NTR gene is associated with depressive
disorder and attempted suicide in Japan (Kunugi et al. 2004)
as well as in China (Gau et al. 2008). This polymorphism in
exon IV gives rise to an amino acid change of serine to leucine
at codon 205 (S205 L) which alters the function of the
p75NTR (Kunugi et al. 2004). Since major depression has
an impact on hippocampal structure and functioning, the anal-
ysis of the hippocampus of mice deficient for p75NTR may
help to gain further insight into the role of this receptor in the
adult hippocampal formation. The first description of
p75NTR knockout mice was published by Lee et al. (1992).
These mice were also termed p75NTRExonIII (von Schack
et al. 2001). They not only display deficits in the peripheral
nervous system (Lee et al. 1992), but also increased basal
forebrain cholinergic neuron size, choline acetyltransferase
activity, and cholinergic target innervation (Yeo et al.
1997).It has been found that the p75NTRExonIII knockout mice
still express a short variant of the p75NTR (von Schack et al.

2001). For a complete knockout of p75NTR another mouse
line was created, the so-called p75NTRExonIV knockout mice.
In these mice, the full-length as well as the truncated p75NTR
are not expressed. Both these p75NTR knockout lines are the
most widely used mouse models that display a deficiency for
p75NTR. However, a pro-apoptotic fragment of p75NTR
seems to be still expressed in the p75NTRExonIV knockout
mice (Paul et al. 2004). In contrast to homozygous BDNF or
trkB knockout mice, homozygous p75NTR knockout mice
(p75NTRExonIII), as well as p75NTRExonIV knockout mice,
survive into adulthood. Deficiency of p75NTR in these differ-
ent mouse lines has been reported to increase the density of
cholinergic fibers within the hippocampus (Dokter et al. 2015;
Poser et al. 2015), dendritic spine densities of CA1 pyramidal
neurons in vitro (Zagrebelsky et al. 2005) and to increase
dendritic spine densities of mature granule cells of the DG
(Dokter et al. 2015). However, whether deletion of p75NTR
has an effect on adult neurogenesis is still controversially
discussed (Bernabeu and Longo 2010; Catts et al. 2008;
Colditz et al. 2010; Dokter et al. 2015; Martinowich et al.
2012).
Sortilin
Mature BDNF mainly acts through two different receptors, the
high-affinity tyrosine kinase receptor B (trkB) and/or the low-
affinity receptor p75NTR. Both BDNF and trkB are highly
expressed in hippocampal formation. Thus, the receptor main-
ly expressed in the hippocampus is trkB, whereas the over-all
expression of p75NTR seems to be very low. However,
p75NTR can form functional receptor complexes with trk re-
ceptors as well as with sortilin (Teng et al. 2010), and p75NTR
not only binds neurotrophins but also pro-neurotrophins. In
contrast to the weak expression of p75NTR, the co-receptor
sortilin is highly expressed in the hippocampus, and there is
strong sortilin immunoreactivity seen in the soma and den-
drites of neurons located in areas CA1–CA3 and within the
DG (Sarret et al. 2003). In that context, it should be mentioned
that sortilin not only interacts with p75NTR but also with
other signaling pathways, including those of neurotensin, cil-
iary neurotrophic factor, spadin (the pro-peptide of sortilin),
and pro-granulin (Nykjaer and Willnow 2012). In 2009,
sortilin-deficient mice were created (Zeng et al. 2009). Using
these mice, it has, e.g., been shown that there is evidence to
suggest that sortilin also interacts with trkA, trkB and trkC
receptors (Vaegter et al. 2011).
Pro-nerve growth factor (pro-NGF) inhibits adult
neurogenesis in the hippocampus (Guo et al. 2013), and cre-
ates a signaling complex by simultaneously binding to
p75NTR and sortilin (Nykjaer et al. 2004). Likewise, pro-
BDNF can induce specific biological effects that are also de-
pendent on the cellular co-expression of both p75NTR and
sortilin (Teng et al. 2005).
Cell Tissue Res
Disturbed BDNF functioning affects
the hippocampal formation
Several studies have reported links between obesity and cog-
nitive dysfunction, and there is evidence that links being obese
to cognitive decline across lifespan (see for review e.g.
(Martin and Davidson 2014)). In addition, it has been reported
that obesity is associated with brain atrophy in humans
(Gustafson et al. 2004; Willette and Kapogiannis 2015).
Recent evidence suggests that BDNF regulates food intake
and the control of body weight, and several studies have indi-
cated that the Val66Met polymorphism in humans is associat-
ed with increased body mass index (BMI) in different coun-
tries (Hong et al. 2012; Skledar et al. 2012). For gaining more
insight into this, different mouse models related to BDNF
signaling have been analyzed. For example, data obtained
from heterozygous BDNF knockout mice indicate that there
is a specific hippocampal volume reduction (Lee et al. 2002;
Magarinos et al. 2011). Interestingly, heterozygous trkB mice
also display a reduction in hippocampal volume (von Bohlen
und Halbach et al. 2003), whereas p75NTR-deficient mice did
not show a hippocampal volume reduction (Dokter et al.
2015). Based on these results, it can be speculated that there
is a link between hippocampal volume and BDNF signaling
via trkB. Curiously, heterozygous BDNF-deficient mice be-
come obese over time as compared to controls (Kernie et al.
2000), as also do trkB-deficient mice (Liao et al. 2013).
Obesity has not only been associated with volume reductions
in the brain (Willette and Kapogiannis 2015) but also with
reductions in adult hippocampal neurogenesis. Impaired adult
hippocampal neurogenesis can be observed in obese mice
(Boitard et al. 2012; Park et al. 2010; Tozuka et al. 2009).
This may indicate that a link between alterations in the
BDNF system and obesity exists. Indeed, mice receiving a
high fat diet become obese over time, and it has recently been
shown that these mice display depressive-like behavior
(Sharma and Fulton 2013; Yamada et al. 2011).
As mentioned above, there is an association of the
Val66Met polymorphism with obesity (Hong et al. 2012;
Skledar et al. 2012), and brain volume reduction can be cor-
related with obesity. Along that line, patients carrying the
BDNF Val66Met polymorphism often display a hippocampal
volume reduction (Cao et al. 2016; Joffe et al. 2009). Thus,
signaling via BDNF may play an important role in the main-
tenance of the postnatal brain, and disturbances in the BDNF
signaling can contribute to morphological changes that may
be associated with pathophysiological conditions.
BDNF and major depression
Polymorphisms in the BDNF gene seem not only to be asso-
ciated with smaller hippocampal volume but also to major
depression (Frodl et al. 2007; Gonul et al. 2011). Several
Cell Tissue Res
reports confirm this observation (Gonul et al. 2011), whereas
in other studies no association between this BDNF Val66Met
polymorphism and reduced hippocampal volumes in major
depression has been detected (Harrisberger et al. 2015;
Jessen et al. 2009).
As early as 1999, Tony Altar proposed that drugs that se-
lectively stimulate the production of neurotrophins could rep-
resent a new generation of antidepressants (Altar 1999).
Several studies have convincingly demonstrated that reduced
levels of BDNF can contribute to major depression. Based on
the evidence that links neuronal plasticity and neurotrophin
signaling in mood disorders, and the fact that BDNF signaling
appears to be both necessary and sufficient for the behavioral
effects produced by antidepressant drugs, it has been sug-
gested that antidepressant treatments may, through enhanced
BDNF signaling, improve the ability of critical brain circuits
to respond optimally to environmental demands, a process that
may be critical in the recovery from depression (Castren and
Rantamaki 2008). Indeed, diverse antidepressants have been
shown to activate receptor trkB and induce PLCgamma signal-
ing pathways, at least in the mouse brain (Rantamaki et al.
2007). However, this would imply that patients suffering from
major depression should have reduced levels of BDNF.
Indeed, several studies show that reduced levels of BDNF,
as well as polymorphisms in the BDNF gene, are associated
with major depression. Moreover, it has been reported that
low plasma BDNF levels are associated with suicidal behavior
in major depression (Kim et al. 2007). Likewise, reduced
BDNF levels were detected in post-mortem brains (within
the hippocampus and prefrontal cortex) of suicide victims
(Karege et al. 2005). Moreover, in another study, a decreased
mRNA and protein expression of BDNF and trkB has been
measured in the hippocampus from suicides’ post-mortems
(Banerjee et al. 2013). This indicates that reduced levels of
BDNF correlate with major depression. Along this line, in the
parietal cortex of post-mortem patients with major depressive
disorder (MDD) who received antidepressant medication, el-
evated levels of BDNF and NT3 have been measured as com-
pared to MDD-untreated patients and controls (Sheldrick et al.
2017). In contrast to BDNF and trkB, the protein and serum
levels of pro-BDNF, sortilin and p75NTR were higher in pa-
tients with MDD (Zhou et al. 2013). However, concerning the
effects of antidepressant treatment on BDNF levels it seems
that different types of antidepressants appear to induce differ-
ential effects on the BDNF levels (Zhou et al. 2017).
Fluoxetine treatment, e.g., increases BDNF expression and it
is thought that the beneficial effect of fluoxetine treatment
against psychological stress is mediated by increasing
BDNF expression in specific brain areas, including the hippo-
campal formation, in rats (Li et al. 2017).
The volume of the hippocampus, as well as the prefrontal
cortex and temporal cortex, were found to be reduced in sui-
cidal psychiatric patients (Gosnell et al. 2016), hinting that
these brain structures may play an important role in major
depression associated with suicide. However, concerning the
hippocampus, reductions in hippocampal volume can already
be seen in patients suffering from major depression (Mervaala
et al. 2000; Xia et al. 2004). How can the hippocampal for-
mation shrink? One possibility is that massive cell loss is
occurring, so that the volume reduction is due to the loss of
neurons. By chance, no major neuronal cell loss has been
detected (Muller et al. 2001). In a rat model of depression, cell
loss was only observed in the DG of female rats, but not of
male rats due to prenatal restraint stress (Schmitz et al. 2002).
Thus, cell loss may occur under very specific conditions in the
DG. Depression is also accompanied by a reduction in the rate
of adult hippocampal neurogenesis, and treatment with anti-
depressants has been shown to increase adult neurogenesis
(Dokter and von Bohlen und Halbach 2012; Veena et al.
2011). Volume reductions may be caused by structural alter-
ations of hippocampal neurons. At least for anterior cingulate
pyramidal neurons, altered dendritic branching has been de-
tected in depressed suicides post mortem (Hercher et al.
2010).
Correlations between the BDNF system
and the dendritic spines in the hippocampus
It is thought that spine densities reflect the excitatory input
densities (Konur et al. 2003), since some forms of
hippocampus-dependent learning as well as hippocampal
LTP have been associated with increased spine densities in
the hippocampus (Engert and Bonhoeffer 1999; Leuner and
Shors 2004). For example, spatial learning is known to in-
crease dendritic spine densities of basal dendrites that stem
from CA1 pyramidal neurons (Moser et al. 1994). Likewise,
associative memory formation increases dendritic spine den-
sities in area CA1. Interestingly, this effect was also restricted
to the dendritic spines of basal dendrites (Leuner et al. 2003).
Concerning the hippocampal dendritic spines, it has also been
shown that aging has a negative effect on dendritic spine den-
sities in area CA1 as well as on spatial memory (von Bohlen
und Halbach et al. 2006b).
BDNF is one of the factors triggering the increase in spine
densities in area CA1 (Alonso et al. 2004). In contrast to its
actions on cortical pyramidal neurons (Horch and Katz 2002),
BDNF in the hippocampus increases the total length, but not
the branching, of apical dendrites within the CA1 stratum
radiatum, without affecting basal dendrites in the stratum
oriens (Alonso et al. 2004). Both the selective increases in
dendrite length and spine densities can be triggered by
BDNF. Thus, BDNF induced by LTP might be responsible
for long-lasting changes in neuronal plasticity by inducing
morphological changes on the (sub)-cellular level. This would
suggest that BDNF is an important player involved in the

modulation of long-lasting effects induced by neuronal plas-
ticity. This would further imply that BDNF expression within
the hippocampus can be modulated by mechanisms related to
learning and memory. Indeed, it has been shown that BDNF
expression is rapidly and selectively induced during
hippocampus-dependent contextual learning (Hall et al.
2000). In contrast, heterozygous BDNF knockout mice dis-
play deficits in spatial memory in the Morris water maze
(MWM) test (Petzold et al. 2015). It has also been shown that
rats learning a spatial memory task in the MWM show elevat-
ed expression of BDNF (Vaynman et al. 2004) and its receptor
trkB (Gomez-Pinilla et al. 2001). Furthermore, MWM-
training can lead to a transient increase in dendritic spine den-
sities (O’Malley et al. 2000). Thus, BDNF is an important
factor that is involved in the regulation of hippocampal spine
densities and spine shape, and these effects seemed to be me-
diated by the signaling of BDNF via trkB receptors, since,
e.g., trkB-deficient mice display reductions in the densities
of hippocampal dendritic spines (von Bohlen und Halbach
et al. 2006a; von Bohlen und Halbach et al. 2008). The mech-
anisms underlying the effects of BDNF on dendritic spines is
not fully understood, since the actions of BDNF can be di-
verse and may not only be regulated by the classic signaling of
BDNF via its receptors. Thus, by using specific knockout
mice lacking BDNF production from exosn 1, 2, 4, or 6 splice
variants, it was found that loss of BDNF from different BDNF
mRNA variants differentially affected dendritic complexity
and spine morphology in the hippocampus (Maynard et al.
2017). Together, these and other results hint at a crucial role
of BDNF and trkB in plastic changes on the level of dendritic
spines.
On the structural level, neuronal plasticity in the hippocam-
pus is not only evident on the level of dendritic spines but also
on the level of adult neurogenesis taking place in the DG.
Adult neurogenesis in the hippocampus can be enhanced by
hippocampus-dependent learning as well as by voluntary ex-
ercise. Long-term exercise not only elevates the rate of adult
neurogenesi, but also BDNF levels (Marlatt et al. 2012) and
pro-BDNF levels in the hippocampus (Ding et al. 2011).
Voluntary exercise also increases the activity of tPA, a serine
proteinase shown to facilitate pro-BDNF cleavage into mature
BDNF (Ding et al. 2011). This suggests that the beneficial
effects on adult neurogenesis depend on mature BDNF, which
can signal through trkB. Contrary to the beneficial effects of
mature BDNF on neurogenesis, pro-BDNF seems to attenuate
adult neurogenesis in the hippocampus (Chen et al. 2016).
Hippocampal LTP also depends, like other forms of long-
lasting neuronal plasticity, on the synthesis of new proteins. In
detail, LTP can be subdivided into two distinct phases. The
early LTP is short lasting (about 1 h) and requires post-
translational modification of synaptic proteins, but is indepen-
dent of protein synthesis. Late LTP represents the long-lasting
phase of LTP that is both translational- and transcriptional-
Cell Tissue Res
dependent (Reymann and Frey 2007; Voronin et al. 1995).
The de novo gene transcription and protein synthesis seem
to enable the formation of dendritic spines (Engert and
Bonhoeffer 1999). As outlined above, LTP seems to be asso-
ciated with increased spine densities (Muller et al. 2000),
whereas LTD has been found to be associated with declines
in spine densities (Monfils and Teskey 2004).
It is known that, during the establishment of LTP, the ex-
pression of several genes, including BDNF, is induced (Hall
et al. 2000). Given that BDNF and trkB are necessary for
neuronal plasticity, including LTP, a local release of BDNF
would be required as well as a specific trkB activation nearby.
By monitoring TrkB activity in single dendritic spines of CA1
pyramidal neurons in response to LTP induction, an autocrine
signaling mechanism involving NMDAR–CaMKII-depen-
dent BDNF release from stimulated dendritic spines and sub-
sequent TrkB activation on these same spines has been ob-
served (Harward et al. 2016).
LTD, a long-lasting reduction in synaptic transmission, has
been found to decrease spine densities and can be modulated
by factors including stress, environment, age and neurotrophic
support (Pinar et al. 2017). Treatment of hippocampal slices
with BDNF attenuated LTD at Schaffer collateral–CA1 syn-
apses (Ikegaya et al. 2002). In contrast, pro-BDNF, by activa-
tion through p75NTR, seems to be capable of facilitating hip-
pocampal LTD, and deletion of p75NTR in mice selectively
impairs pro-BDNF-mediated LTD (Woo et al. 2005). Thus,
together with the finding that BDNF promotes synaptic po-
tentiation via trkB receptors, a bidirectional regulation of syn-
aptic plasticity by pro-BDNF (via p75NTR) and mature
BDNF (via trkB) could be suggested. The effects of BDNF
in this context have been studied by several groups, but the
action of pro-BDNF acting through p75NTR is currently still
not well understood. Analysis in that direction has been ham-
pered by the lack of a suitable model. Recently, a cleavage-
resistant pro-BDNF knockin mouse has been generated (Yang
et al. 2014). Using this mouse model, it has also been shown
that pro-BDNF impairs LTP and negatively regulates hippo-
campal dendritic complexity and spine density through
p75NTR (Yang et al. 2014). This knockin mouse model might
also be helpful for gaining further insight into the roles of pro-
BDNF in hippocampal formation. The results of that study
suggest that signaling through p75NTR is responsible for the
effects on spine densities. Indeed, lack of p75NTR in the mu-
rine hippocampus leads to a reduction in spine densities
(Dokter et al. 2015; Zagrebelsky et al. 2005), as outlined
above in Bp75 neurotrophin receptor (p75NTR)^.
Pro-BDNF is enzymatically cleaved to generate mature
BDNF and its pro-peptide. BDNF pro-peptide is also biolog-
ical active and alters neuronal plasticity within the hippocam-
pus. BDNF pro-peptide facilitates hippocampal LTD through
a mechanism also involving p75NTR (Mizui et al. 2015).
Moreover, it has been shown that exposure of BDNF pro-
Cell Tissue Res
peptide to mature hippocampal neurons in culture dramatical-
ly reduced dendritic spine density via caspase-3 (Guo et al.
2016). Thus, BDNF and pro-BDNF not only have an impact
on neuronal plasticity within the hippocampus, thereby affect-
ing the morphology and number of dendritic spines, but so
does the BDNF pro-peptide.
The mechanism of major depression and the neurobiolog-
ical basis of antidepressant therapy are still largely unknown.
There is accumulating evidence that implicates adult hippo-
campal neurogenesis in the pathophysiology of depression.
Psychosocial stress reduces neurogenesis in rodents, whereas
chronic treatment with antidepressants increases neurogenesis
and blocks the effects of stress (Dranovsky and Hen 2006;
Kempermann and Kronenberg 2003; von Bohlen und
Halbach 2010b). BDNF has been described as a factor playing
an important role in major depression, and antidepressants
seem to activate BDNF signaling through trkB. Major depres-
sion induces loss of hippocampal volume and reductions in
the rate of adult neurogenesis. However, adult neurogenesis is
not only affected in depression but it is also known that spine
reductions in the hippocampus are associated with mood dis-
orders (Law et al. 2004; Rosoklija et al. 2000). Furthermore,
there is evidence to suggest that antidepressant treatment is
capable of increasing spine density in the hippocampal area,
CA1 (Norrholm and Ouimet 2001). Interestingly, depressive-
like behavior of rats not only results in a reduction in spine
densities in area CA1 but also in a decrease in the hippocam-
pal ratio of BDNF/pro-BDNF (Qiao et al. 2014). Injection of
BDNF into area CA1 in stressed rats reduced depressive-like
behaviors and prevented the loss of dendritic spines (Qiao
et al. 2017). In contrast, injection of exogenous pro-BDNF
into the CA1 region of naive rats caused depressive-like be-
havior and a decrease in spine densities (Qiao et al. 2017).
Thus, disturbed structural neuronal plasticity is associated
with depression, and treatment with antidepressants can con-
tribute to repair mechanisms in the hippocampus.
Inappropriate neurotrophic support could lead to structural
disorganization in the brain, and ultimately to a decreased
brain capacity (Angelucci et al. 2005), whereas antidepressant
treatment is capable of increasing BDNF mRNA levels in the
brain (Altar 1999). BDNF is not the sole mediator of depres-
sion or anxiety, but might represent a target of antidepressant-
induced effects (Martinowich et al. 2007). BDNF in the hip-
pocampus may represent a key factor involved in the regula-
tion of neuronal plasticity and reorganization of synaptic con-
tacts, and increasing BDNF levels in the hippocampal forma-
tion may have beneficial effects on neuronal plasticity, learn-
ing and memory.
Voluntary physical exercise, like an enriched environment,
increases expression of BDNF in the hippocampus (Sølvsten
et al. 2016), as well as hippocampal neurogenesis (Fabel et al.
2009) and dendritic spine densities within the hippocampus
(Stranahan et al. 2009). Moreover, voluntary physical exercise
improves depressive behavior in a rat model of depression
(Eldomiaty et al. 2017). Interestingly, only voluntary physical
exercise, but not forced physical exercise, has beneficial ef-
fects on different hippocampus-dependent behavioral tests in
rats (Burghardt et al. 2004) and on hippocampal BDNF levels
(Ke et al. 2011). Thus, voluntary physical exercise in a stim-
ulating environment may have a positive effect on BDNF
levels, exerting a positive effect on neuronal plasticity.
Voluntary physical exercise in a stimulating environment
may not only be helpful for increasing the morphological sub-
strates for neuronal plasticity but may even represent a strate-
gy for the prevention of major depression.
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