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Secretory trafficking in neuronal dendrites

April C. Horton and Michael D. Ehlers

The neuronal secretory pathway represents the intracellular route for proteins involved in synaptic transmission and plasticity, as
well as lipids required for outgrowth and remodelling of dendrites and axons. Although neurons use the same secretory
compartments as other eukaryotic cells, the enormous distances involved, as well as the unique morphology of the neuron and its
signalling requirements, challenge canonical models of secretory pathway organization. Here, we review evidence for a
distributed secretory pathway in neurons, suggest mechanisms that may regulate secretory compartment distribution, and
discuss the implications of a distributed secretory pathway for neuronal morphogenesis and neural-circuit plasticity.

One hundred and six years ago, the Italian anatomist Camillo Golgi
announced the discovery of an ‘internal reticular apparatus’ in nerves
of the spinal cord ganglia1, a finding from which a century of organelle
biology has emerged. Golgi’s student, Adelchi Negri, proceeded to
show that the internal reticular apparatus (at first dismissed as a possi-
ble artefact) was, in fact, a universal structure present in almost all cell
types. Since then, the Golgi apparatus has been shown to be crucial for
the processing of proteins and lipids along the secretory pathway. For
the most part, the structure, subcellular distribution and functions of
the Golgi apparatus (and associated secretory compartments) have
been uncovered experimentally in relatively simple cells such as fibrob-
lasts. Ironically, the cell whose Golgi apparatus has received the least
attention is the one in which it was first discovered — the neuron.
The lag in understanding the neuronal Golgi, and neuronal secretory
trafficking in general, is understandable given the problems inherent in
studying neuronal cell biology. Neurons have an extremely complicated
geometry, with axons extending great distances from the cell body and
pleiomorphic dendrites full of intracellular membranes with poorly
understood functions. An additional complication comes from the sheer
scale over which this pathway must operate. Neurons are immense, with
surface areas up to 10,000 times greater than most other cells (Fig. 1).
The precise localization of membrane proteins over this vast surface area
is essential for formation of elaborate neural networks. Similarly,
secreted soluble proteins that are important for regulating neuronal sur-
vival and morphology, must also proceed through these secretory path-
way compartments before being released. Furthermore, lipids
synthesized along the secretory pathway must be inserted into the
plasma membrane at specific locations to allow dendritic outgrowth and
branching to respond to local signals. Secretory trafficking is involved in
a number of highly specialized neuronal functions; nevertheless, until
recently almost everything known about neuronal secretory trafficking
April C. Horton is in the Department of Neurobiology, Duke University Medical
Center, Box 3209 Durham, NC 27710, USA. Michael D. Ehlers is in the
Department of Neurobiology, Department of Cell Biology, Department of
Pharmacology and Cancer Biology, and the Neuroproteomics Laboratory, Duke
University Medical Center, Box 3209 Durham, NC 27710, USA.
e-mail: ehlers@neuro.duke.edu
was inferred from studies of non-neuronal cells. This review addresses
how the spatial organization of neuronal secretory organelles both mir-
rors and differs from other cell types. We consider what signals regulate
the distribution of neuronal secretory organelles, particularly the Golgi,
and how secretory trafficking contributes to dendritic outgrowth,
synaptogenesis and synaptic plasticity. Although the proper localization
of membrane proteins may involve the targeting of mRNAs to dendrites,
this review focuses exclusively on trafficking events that occur after pro-
tein synthesis. Readers are referred to recent reviews of mRNA traffick-
ing and protein synthesis in dendrites2,3.
Spatial organization of neuronal secretory compartments
The primary organelles of the secretory pathway include the endoplasmic
reticulum, the Golgi apparatus and the trans-Golgi network (TGN;
Fig. 2). As in non-neuronal cells, the neuronal endoplasmic reticulum is a
continuous endomembrane that extends throughout the cell, function-
ing as both an intracellular calcium signalling compartment, as well as the
site of synthesis for membrane proteins involved in neuronal signalling4.
The surface expression of a number of important neuronal proteins5–10 is
known to be regulated by endoplasmic reticulum retention/retrieval or
export signals. A subset of these regulatory signals functions at endoplas-
mic reticulum exit sites9 — specialized ribosome-free subdomains of
synthetic endoplasmic reticulum membrane where cargo is concentrated
into vesicles that bud from the endoplasmic reticulum and are trans-
ported to the Golgi11. Much like endoplasmic reticulum exit sites visual-
ized in non-neuronal cells12,13, neuronal endoplasmic reticulum exit sites
are evident at the microscopic level as stable, stationary puncta distrib-
uted on the endoplasmic reticulum membrane throughout the cell,
including throughout dendrites (Fig. 3)14,15.
After exit from the endoplasmic reticulum, secretory trafficking in
neurons diverges from the canonical secretory pathway organization.
In most cells, cargo buds from endoplasmic reticulum exit sites
extending throughout the cell and is transported inwards to a perinu-
clear Golgi apparatus (Fig. 2), a requisite station for processing and
sorting16. From the Golgi, cargo is directed back to its final cellular des-
tination. In this way, the subcellular location of the Golgi dictates the
directionality of both pre- and post-Golgi secretory trafficking.

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Epithelial
cell
40 µm
Neuron
Figure 1 Neurons have an immense and complex plasma membrane. A
pyramidal cortical neuron labelled by the Golgi reaction shows the
remarkable size and complexity of the neuronal plasma membrane. This
neuron has an elaborate and polarized dendritic arbor (red arrow), with both
apical and basolateral dendrites. These dendrites have hundreds of
protrusions, called spines (inset), which function as sites of excitatory
synaptic contact. Furthermore, the neuron has a specialized axon (blue
arrow) that can extend many hundreds of microns to carry action potentials to
targets far from the cell body. Such exquisite morphological and functional
specialization demands mechanisms of secretory trafficking that may differ
substantially from those in much smaller and simpler non-neuronal cells,
such as the typical epithelial cell depicted. Adapted from ref. 100.
In contrast to the typical central or perinuclear distribution of the
Golgi in most non-neuronal cells, neurons have both somatic and den-
dritic Golgi compartments (Fig. 4)14,17,18. Dendritic Golgi elements
have been visualized both ultrastructurally17, 18 and by live-cell imag-
ing14. These dendritic Golgi (termed ‘Golgi outposts’) are discrete
compartments that are discontinuous with somatic Golgi18, although
they share the same molecular markers. For example, presumptive
Golgi membranes in dendrites have been immunogold-labelled for the
Golgi proteins TGN3817, α-mannosidase II, giantin, and rab6 (ref. 18).
Moreover, both dendritic and somatic Golgi process secretory cargo14.
Despite the many similarities between somatic and dendritic Golgi,
important differences exist: for example, dendritic Golgi characterized
by immunogold electron microscopy occur within dendritic spines18,
whereas those identified by live imaging are evident mainly in den-
dritic shafts14. In addition, live-cell imaging experiments have shown
that pre-Golgi carriers trafficking in dendrites occasionally bypass
dendritic Golgi and are transported instead to somatic Golgi14, high-
lighting the intriguing possibility that dendritic Golgi could, in fact, be
specialized to handle a subset of secretory cargo. However, there is no
direct evidence that dendritic Golgi outposts have a specific functional
significance. In either case, the dispersed Golgi in dendrites identifies a
novel secretory pathway organization that may underlie the ability of
isolated dendrites to glycoslyate newly synthesized membrane pro-
teins19, and to synthesize and express exogenous membrane proteins at
the plasma membrane after dendrite transection20,21. Important ques-
tions remain about these compartments — such as how do they origi-
nate, what regulates their dispersal, and what secretory abilities do they
confer upon dendrites?
Regulation of dendritic Golgi dispersal
The question of how Golgi outposts originate in dendrites may be
586
©2004 Nature Publishing Group
Plasma membrane
Trans-Golgi network
Golgi
Nucleus
ER–Golgi intermediate
compartment
ER exit sites
ER
Figure 2 Secretory pathway components. (a) The endoplasmic reticulum
(ER) — a mesh-like endomembrane that is continuous with the nuclear
envelope — extends to the cell periphery and is the site of lipid and
membrane protein synthesis. Both secreted and membrane proteins, as well
as lipids, exit the ER at specialized ribosome-free sub-domains, termed ER
exit sites. These exit sites are coated with COPII components such as
Sec23–Sec24 and Sec13–Sec31 (red). After exit from the ER, cargo is
segregated into ER–Golgi transport vesicles characterized by components of
the COPI coat (blue) in the ER–Golgi intermediate compartment. From the
ER, cargo is transported inwards towards the Golgi apparatus. Cargo
continues through the Golgi and the TGN en route to the plasma membrane.
informed by examples of Golgi dispersal in non-neuronal cells. In
many cell types, there is precedent for the growth and redistribution of
the Golgi during times of peak secretory activity. For example, in the
protozoan parasite Giardia lamblia, the Golgi apparatus is not evident
for much of the cell cycle22. During differentiation and secretion of
cyst-wall components, however, specialized secretory organelles
termed encystation-specific vesicles (ESVs) appear23. These ESVs rep-
resent a primitive Golgi that has hypertrophied to meet the secretory
demands of the organism24. Given that Golgi outposts are present in
only a subset of dendrites14, one interesting possibility is that the dis-
persal of Golgi into dendrites increases and decreases depending on
local secretory demands.
Cell division represents one physiological process requiring the for-
mation of new Golgi elements. During mitosis, each daughter cell
inherits a Golgi complex, or at least the material for constructing one.
Exactly how this occurs depends on the cell type (Fig. 5). In the intra-
cellular parasite Toxoplasma gondii, the Golgi grows with the cell and
undergoes lateral fission during cell division (Fig. 5a)25. In mammals,
the Golgi breaks down into vesicular fragments during mitosis
(Fig. 5b)26–28. Numerous signalling events are implicated in this frag-
mentation, including phosphorylation of structural proteins of the
Golgi matrix and vesicle tethering proteins, resulting in the breakdown
of Golgi superstructure29. Golgi proteins then pass between the daugh-
ter cells in a process regulated by microtubules at the centrosome28,29,
and the membranes re-stack into a recognizable Golgi minutes after
cytokinesis27,30. This re-stacking is accompanied by a rapid reversal of
the phosphorylation events preceding metaphase31. Neurons do not
undergo mitosis; however, given the robust and dynamic nature
through which numerous kinases regulate Golgi structure, we propose
that phosphorylation cascades may regulate Golgi dispersal in the neu-
ron. In this scenario, a phosphorylation event would result in the dis-
persal of Golgi matrix into dendrites, either by diffusion through the
cytosol or transport along microtubules32. Just as the proteinaceous
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a dendritic Golgi form de novo around dendritic endoplasmic reticulum
b
Sec13
Sec24−YFP
Figure 3 ER exit sites are distributed throughout neuronal and non-neuronal
cells. (a) A high-magnification view of a HeLa cell stained for the COPII
protein Sec13 identifies punctate ER exit sites (red, representative
examples are indicated by arrowheads) associated with ER membrane
throughout the cell, including the cell periphery. Scale bar represents 10
µm. Reproduced from ref. 12 © 2000 by permission of Mol. Biol. Cell and
the American Society for Cell Biology. (b) Staining for Sec13 (red, top) or
expression of yellow fluorescent protein–Sec24 (green, middle) shows that
neuronal ER exit sites are present in dendrites. Colocalizing puncta are
yellow in the merged image (bottom), and representative examples are
indicated by arrowheads. Scale bar represents 5 µm. Reproduced from ref.
14 © 2003 with permission from the The Society for Neuroscience.
Golgi matrix functions as a template for Golgi construction33, this dis-
persed matrix might then function as a template for the formation of a
dendritic Golgi outpost.
Finally, the origination of Golgi in dendrites might be explained by
the fact that endoplasmic reticulum and Golgi membranes exist in a
dynamic equilibrium34. Numerous proteins cycle between the endo-
plasmic reticulum and Golgi35, implying a constant flux of vesicular
traffic from the endoplasmic reticulum to the Golgi and back again.
The co-dependent relationship between endoplasmic reticulum and
Golgi membranes has led to the hypothesis that Golgi elements could
derive de novo from the endoplasmic reticulum36. Indeed, this does
occur in the yeast Pichia pastoris, where discrete Golgi fragments coa-
lesce around endoplasmic reticulum exit sites (Fig. 5c)37. Golgi frag-
ments can form around mammalian endoplasmic reticulum exit sites
when cells are treated with nocodazole to disrupt microtubules
(Fig. 5d)12. In neurons, both endoplasmic reticulum and endoplasmic
reticulum exit sites extend far into the dendrites14,15. Could it be that
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exit sites? To test this model, an examination of the spatial relationship
between dendritic Golgi and dendritic endoplasmic reticulum exit
sites, as well the microtubule-dependence of dendritic Golgi outposts
will be required.
Cytoskeletal influences on Golgi organization
Golgi structure and localization are also intimately related to cytoskele-
tal organization38. The typical perinuclear localization of the non-neu-
ronal Golgi is heavily dependent on endoplasmic reticulum-derived
cargo moving inwards to the Golgi via the minus-end directed micro-
tubule-based motor, dynein. Disruption of microtubules results in
Golgi fragmentation and dispersal39,40, as does functional disruption of
cytoplasmic dynein41,42. In addition to accounting for steady-state
localization of the Golgi, microtubules can also control its dynamic
rearrangements, as occurs when secretory flux becomes orientated in a
particular direction. For example, in migrating fibroblasts, the Golgi
becomes orientated towards the leading edge of the cell43,101. This Golgi
re-orientation occurs concomitantly with a re-organization of micro-
tubules, mediated by the microtubule-binding protein adenomatous
polyposis coli (APC) and the Par6–aPKC polarity complex44. In this
way, cytoskeletal organization and directed secretory flux are simulta-
neously controlled to allow directed addition to the plasma membrane.
Because of the close relationship between microtubule organization
and Golgi location, it is intriguing that microtubule organization in
neurons is quite distinct from that in non-neuronal cells. Rather than
having microtubules with plus ends projecting outwards in a radial
array from a central microtubule organizing centre, microtubules of
mixed polarity are found throughout dendrites45,46. However, axonal
microtubules are orientated exclusively with the microtubule plus ends
distal45. This neuron region-specific microtubule organization scheme
has important implications for the directionality of both polarized
post-Golgi secretory trafficking47 and dynein-mediated endoplasmic
reticulum-to-Golgi trafficking. Whereas endoplasmic reticulum-
derived transport carriers are transported exclusively inwards in non-
neuronal cells48, post-endoplasmic reticulum carriers are transported
bi-directionally in dendrites14 to allow their eventual fusion with den-
dritic Golgi elements14.
Although microtubules are responsible for the gross localization of
the Golgi, there is also emerging evidence for a role of the actin
cytoskeleton in maintaining Golgi integrity and directing secretory
trafficking. Members of the myosin I (ref. 49), myosin II (refs 49, 50),
and myosin VI (ref. 51) families of actin-based motors have all been
found on Golgi membranes in mammalian cells. Indeed, myosin II is
required for budding from the TGN49,50. In addition, the myosin V gene
product Myo2p is important for polarized secretory trafficking in bud-
ding yeast52. These motors may link cargo-containing membranes
directly to the actin cytoskeleton, as well as provide the force necessary
for membrane budding and the power for movement of post-Golgi car-
riers. A link between Golgi structure and a regulator of the actin
cytoskeleton was also identified with the recent discovery of citron-N as
a neuron-specific, Golgi-localized, Rho-binding protein53. Interference
of citron-N expression, or microinjection of antibodies to citron-N,
results in Golgi dispersal; similarly, expression of a mutant form of cit-
ron-N that is unable to bind Rho also results in dispersal53. In relation
to Golgi structure, however, these experiments should be interpreted
with caution because of the number of Golgi-localized proteins that
can cause Golgi fragmentation when overexpressed or sup-
pressed41,54–57. Nevertheless, the possibility that local actin remodeling
regulates neuronal Golgi dispersal, possibly leading to the formation of
discrete Golgi outposts in dendrites, is an exciting new development.
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a b 1
c
GalTase
VSVG
Merge
Figure 4 Neurons have both somatic and dendritic Golgi. (a) One of Golgi’s
first drawings of the internal reticular apparatus of a cerebellar Purkinje cell
(adapted from ref. 1). (b) Immunogold labelling of rat hippocampal neurons
highlights structures in postsynaptic dendritic spines (‘S’, panels 1 and 2)
labelled for the Golgi proteins α-mannosidase II (frame 1) and giantin (frame
2). Red arrowheads indicate gold particles. Membrane-bound structures along
dendritic shafts (‘D’, panels 2 and 3) were also labelled for Golgi proteins,
such as the rab6-labelled compartment in frame 3. Scale bars represent 0.25
Secretory trafficking and neuronal morphology
As neurons differentiate and their surface area increases dramatically,
dendritic and axonal outgrowth requires the transfer of large amounts
of membrane from intracellular stores to the plasma membrane58.
Directed axonal outgrowth requires the selective addition of mem-
brane to particular regions of the growth cone59, a process that must be
responsive to local guidance cues60. In an analogous fashion, dendritic
branching most probably involves the regulated addition of lipid to the
plasma membrane, a process that may also be regulated by local sig-
nals. A critical role for the secretory pathway is implied in these
processes, although neuronal morphology has primarily been viewed
through the mechanistic lens of cytoskeletal rearrangements61–63 or
genetic programmes64,65.
In non-neuronal cells, there are numerous examples of directed
secretory flux underlying vectorial addition to the plasma membrane.
In yeast, secretory traffic is directed towards the growing bud66. In
mammals, the Golgi apparatus in activated natural killer cells becomes
re-orientated towards the target cell67,68. Similarly, in migrating
fibroblasts, the Golgi becomes orientated to direct secretory flux in the
direction of migration43,69,101. In his later studies in gastric mucosal
cells, Golgi himself noted that the apparatus was directed towards the
secretory surface, and most probably served a secretory function70.
Each of these examples highlights a role for directed secretory flux in
dynamic cellular events. Certainly the morphological changes accom-
panying neuronal migration, differentiation and process outgrowth
also involve highly dynamic changes in cyto-architecture. Unlike
fibroblasts or yeast cells, which have largely stereotyped morphologies,
neurons adopt literally thousands of different shapes, each highly spe-
cialized for various signalling functions and for incorporation into neu-
ral circuits71. However, it is unclear whether and how the organization
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2 3
µm. Reproduced from ref. 18 © 2003 with permission from Elsevier. (c) Live-
cell imaging experiments with cultured rat hippocampal neurons highlights
both somatic and dendritic Golgi structures positive for cyan-fluorescent-
protein-labelled galactosyltransferase (GalTase, green). Less than 20 min after
release from the ER, the secretory cargo protein vesicular stomatitis virus
glycoprotein (VSV-G; red) is transported to both the somatic (left) and dendritic
(right, arrows) compartments. Scale bar represents 5 µm. Reproduced from
ref. 14 © 2003 with permission from the The Society for Neuroscience.
of the secretory pathway influences neuronal morphology. Could den-
dritic Golgi allow secretory flux to respond to local cues, and thus
underlie dendritic branching and outgrowth patterns during neuronal
development? Indeed, Golgi outposts are present in only a subpopula-
tion of dendrites and are most prevalent in primary dendrites14, sug-
gesting regional differences (for example, proximal versus distal
dendrites) in the transport of membrane and cargo through the secre-
tory pathway. Finally, how does the secretory pathway maintain neu-
ronal morphology in the face of the continual endocytosis in dendrites
and at synapses72? Answers to these questions will be central to advanc-
ing our limited understanding of neuronal membrane homeostasis,
and may hold the key to understanding how neurons take their shape.
Secretory trafficking, synaptogenesis and synaptic plasticity
The formation of a new synapse requires the delivery of both pre- and
post-synaptic membrane components to the site of axo-dendritic con-
tact73, a process that necessarily begins along the secretory pathway. We
now discuss recent evidence regarding the role of the secretory path-
way in synaptogenesis and in the dynamic trafficking events that
underlie activity-dependent synaptic plasticity.
Presynaptic differentiation requires that the protein machinery nec-
essary for neurotransmitter vesicle release and recycling, as well as for
cytoskeletal components of the active zone, be transported to the
presynaptic nerve terminal. At least two distinct types of carriers
responsible for transport of these presynaptic elements have been
characterized. Green fluorescent protein (GFP) fusions with the presy-
naptic vesicle proteins synaptophysin and VAMP, are transported in
approximately 1-µm pleiomorphic organelles74,75. In contrast, the
cytoskeletal proteins Piccolo and Bassoon (as well as the synaptic
plasma-membrane-associated protein SNAP25, Rab3-interacting
NATURE CELL BIOLOGY VOLUME 6 | NUMBER 7 | JULY 2004

a b
Metaphase
1 4
Prophase
2 5
Telophase
Anaphase
3 6
c d
Figure 5 Examples of Golgi biogenesis and dispersal. (a) Golgi biogenesis in
T. gondii occurs by growth and lateral fission. When the cell prepares to
divide (1), the Golgi (red) hypertrophies (2) and undergoes lateral fission
(3). This occurs again, resulting in multiple Golgi fragments (4). Each
daughter cell inherits two Golgi fragments (5), which coalesce into a single
Golgi (6). (b) During mammalian mitosis, the Golgi ribbon breaks down in
metaphase, and is completely vesiculated by anaphase. The vesiculated
Golgi is then partitioned into each daughter cell. (c) In P. pastoris, discrete
Golgi elements (red) arise de novo around ER exit sites (blue). (d) In the
presence of an intact radial microtubule cytoskeleton (grey lines), the
typical mammalian Golgi (red) has a perinuclear distribution. In the absence
of microtubules (as with nocodazole treatment), the Golgi becomes
fragmented into mini-stacks that are scattered throughout the cytoplasm.
molecule, Munc18, Munc13 and N-cadherin) are transported to the
presynapse by 80-nm dense-core vesicles that exclude synaptic vesicle
proteins such as VAMP2 and synaptophysin76. Although these carriers
transport distinct sets of proteins, both seem to be derived from the
Golgi apparatus76,77. It is important to understand how proteins are
segregated into these carriers, as well as to understand the mechanisms
that target these carriers to specific axonal locations.
Postsynaptic differentiation requires the delivery of neurotransmit-
ter receptors and other membrane proteins to the postsynaptic mem-
brane, although how this occurs is not as well understood. Live
imaging experiments have suggested that in developing cortical neu-
rons, glutamate receptors are transported by transport ‘packets’ of
unclear origin78. However, photobleaching experiments in neurons
expressing GFP fused to the NR1 subunit of the NMDA-type gluta-
mate receptor highlighted a gradual accumulation of the protein at
synapses, rather than quantal vesicular delivery79. Therefore, exactly
how membrane proteins are targeted to synapses remains an open
question, but probably involves a combination of directed post-Golgi
transport combined with diffusion within the plasma membrane and
selective retention at synapses80, 81. Proteins such as microtubule-
based motors82, molecular scaffolds83 and the exocyst complex84,85
associate with vesicular cargo in neurons. Vesicular trafficking may be
a general mechanism for the delivery of membrane components to nas-
cent synapses, as suggested by the observation that vesicular elements
characterized by the Golgi proteins β-COP and γ-adaptin are recruited
to sites of axo-dendritic contact in dendrites, where they are anchored
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through association with the neural cell adhesion molecule N-CAM86.
Additionally, TGN-derived organelles labelled by prolonged exposure
to the dye FM1-43 undergo calcium-dependent exocytosis in den-
drites87,88. Together these experiments suggest a model in which postsy-
naptic signalling proteins are packaged into carriers localized at nascent
synapses through contacts with N-CAM. These carriers have the poten-
tial to undergo calcium-dependent exocytosis, delivering the earliest
components of the postsynapse to sites of axo-dendritic contact.
As in synaptogenesis, postsynaptic delivery of neurotransmitter
receptors occurs during certain forms of synaptic plasticity, specifically
long-term potentiation (LTP)89,90. Activity-dependent strengthening
of the postsynaptic response is caused largely by the exocytotic delivery
of AMPA receptors to the postsynaptic membrane91–93. The synaptic
delivery of AMPA receptors during LTP occurs minutes after the LTP-
inducing stimulus91, raising the question of which cellular storehouse
holds functional AMPA receptors for insertion into synapses. One
potential intracellular organelle is the TGN. In support of this notion,
brefeldin A (which disrupts Golgi trafficking by inhibiting guanine
nucleotide exchange factors for Arf GTPases) decreases NMDA-
induced synaptic potentiation and prevents an NMDA-induced
increase of AMPA receptor expression in synaptic membranes94.
Intriguingly, LTP is a calcium-dependent process95, and calcium-
dependent exocytosis of TGN elements has been demonstrated in den-
drites87,88. However, Golgi outposts are readily detectable in only a
subset of neuronal dendrites14, and the number and availability of
TGN elements in dendrites is uncertain, suggesting that compartments
outside the secretory pathway may contribute to AMPA receptor traf-
ficking during synaptic plasticity. The use of more specific reagents or
molecular tools to selectively block defined stages in secretory traffick-
ing, as well as more detailed high-resolution immunogold electron
microscopy studies, will be required to definitively establish the role of
secretory trafficking in LTP. Nevertheless, determining the source of
AMPA receptors for LTP remains a critical issue in understanding the
cellular mechanisms of learning and memory, and the secretory path-
way may have an important function in this process.
Secretory trafficking and neurological disease
The lack of information on the most basic questions regarding the
localization and regulation of neuronal secretory organelles has hin-
dered the thorough understanding of neurodegenerative diseases,
many of which involve the faulty processing of membrane or secreted
proteins96. This is highlighted by Alzheimer’s disease, in which patho-
logical secretion of Aβ peptides depresses excitatory synaptic transmis-
sion97 and may be involved in the cognitive decline associated with this
disease. Aβ secretion requires association of the integral membrane
amyloid precursor protein with the γ-secretase complex (which
includes presenilin, another membrane protein)98. The physical asso-
ciation of these integral membrane proteins is thought to occur early
in the secretory pathway, but exactly how or where this protein com-
plex formation occurs within the cell, remains poorly understood99.
Advances in determining the pathogenesis of this and other neurode-
generative diseases will require an understanding of the core secretory
machinery in dendrites.
Unresolved questions
Much work remains in understanding neuronal secretory trafficking,
its unique organization and regulation, and its specialized functions in
these highly complex cells. Regulating Golgi dispersal throughout den-
drites or axons may represent a means for regulating secretory capac-
ity. Simple questions regarding the nature of Golgi outposts, such as
whether they are complete Golgi stacks with cis- and trans- faces, await
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Golgi dispersal into neuronal dendrites
How?
• Phosphorylation events resulting in release of
somatic Golgi matrix and transport into dendrites
• De novo biogenesis resulting from the cycling
of Golgi proteins through dendritic ER exit sites
• Transport via microtubule
or actin-based motors
• Hypertrophy of existing secretory
elements in response to local cues
Figure 6 Potential mechanisms for dendritic Golgi formation and proposed cellular functions.
ultrastructural examination. It is important to identify how a neuron
controls whether dendrites contain Golgi outposts, and what estab-
lishes the location of Golgi outposts. For example, are Golgi outposts
located only within large, proximal dendrites, or are they also located
in distal dendrites in closer proximity to synapses? Furthermore, it
remains to be determined which cargo use Golgi outposts rather than
somatic Golgi, and what the role of Golgi outposts is in relation to
synapse modification and dendrite growth (Fig. 6). Finally, a re-orien-
tation of the secretory apparatus and polarized secretory flux may
underlie dendritic outgrowth, but we have very little knowledge of
how the secretory pathway functions in developing neurons. Answers
to such basic cell biological questions about neuronal secretory traf-
ficking is critical not only for appreciating normal neuronal function,
but also for understanding the pathological basis of many neurological
diseases involving aberrant protein processing and trafficking. In this
regard, secretory trafficking in dendrites has some distance to go.
ACKNOWLEDGMENTS
We thank the reviewers, as well as T. Blanpied, D. Gitler, J. Hernandez, A. Mizrahi, F.
Wang, and J. Welch, for critical comments and suggestions. In addition, we
apologize to those whose work we did not cite because of space limitations. Work
from the laboratory of M.D.E. is supported by the National Institutes of Health
(NS39402 and MH64748), the Christopher Reeve Paralysis Foundation, and the
Ruth K. Broad Biomedical Research Foundation. A.C.H. is also supported by the
Gertrude Elion Award from the Triangle Community Foundation.
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