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Release of chemical transmitters from cell
bodies and dendrites of nerve cells
rstb.royalsocietypublishing.org
Francisco F. De-Miguel1 and John G. Nicholls2
1
Introduction
Cite this article: De-Miguel FF, Nicholls JG.
2015 Release of chemical transmitters from cell
bodies and dendrites of nerve cells. Phil. Trans.
R. Soc. B 370: 20140181.
http://dx.doi.org/10.1098/rstb.2014.0181
Accepted: 3 April 2015
One contribution of 16 to a discussion meeting
issue ‘Release of chemical transmitters from
cell bodies and dendrites of nerve cells’.
Subject Areas:
neuroscience, cellular biology
Keywords:
extrasynaptic, somatic exocytosis, dendritic
exocytosis, transmitter release, neuron– glia
communication, brain disease
Author for correspondence:
Francisco F. De-Miguel
e-mail: [email protected]
Instituto de Fisiologı́a Celular-Neurociencias, Universidad Nacional Autónoma de México,
Distrito Federal, Mexico
2
Scuola Internazionale Superiore di Studi Avanzati, SISSA, Trieste, Italy
Papers in this issue concern extrasynaptic transmission, namely release of
signalling molecules by exocytosis or diffusion from neuronal cell bodies,
dendrites, axons and glia. Problems discussed concern the molecules, their
secretion and importance for normal function and disease. Molecules secreted
extrasynaptically include transmitters, peptides, hormones and nitric oxide.
For extrasynaptic secretion, trains of action potentials are required, and the
time course of release is slower than at synapses. Questions arise concerning
the mechanism of extrasynaptic secretion: how does it differ from the release
observed at synaptic terminals and gland cells? What kinds of vesicles take
part? Is release accomplished through calcium entry, SNAP and SNARE proteins? A clear difference is in the role of molecules released synaptically and
extrasynaptically. After extrasynaptic release, molecules reach distant as well
as nearby cells, and thereby produce long-lasting changes over large volumes
of brain. Such changes can affect circuits for motor performance and mood
states. An example with clinical relevance is dyskinesia of patients treated
with L-DOPA for Parkinson’s disease. Extrasynaptically released transmitters
also evoke responses in glial cells, which in turn release molecules that cause
local vasodilatation and enhanced circulation in regions of the brain that
are active.
1. Aims of this special issue of Philosophical Transactions of the
Royal Society
The papers collected here present an overview of the mechanism and functional
importance of release from ‘extrasynaptic’ sites. A major objective of this Royal
Society special issue was to promote discussion by people who use cellular, molecular and physiological techniques to study the release of transmitters, peptides
and hormones from neuronal cell bodies, dendrites and glial cells. A further aim is
to analyse the differences and similarities between exocytosis from synapses and
gland cells. A great deal of modern research has been devoted to understanding
transmitter release by presynaptic terminals. Most general knowledge about the
mechanism of transmitter release has come from experiments on neuromuscular
junctions [1] and the squid giant synapse ([2]; for review, see [3,4]), and more
recently from synapses formed by neurons in culture, first obtained between
adult leech neurons [5] and afterwards between other neuron types. Yet, paradoxically, axon varicosities of parasympathetic nerve axons and chromaffin
cells in the adrenal medulla are sites of extrasynaptic release at which chemically
mediated synaptic transmission was postulated for the first time in 1921 by Loewi
[6] and in 1904 by Elliot [7]. Papers in this collection show that release from neuronal and glial cell bodies, dendrites and axons is widespread. It represents a novel
area of research on functional changes in the input–output relationships of the
nervous system that last for days, weeks or months. A feature of ‘extrasynaptic’
release, in addition to its prolonged time course, is the widespread transmission
of signalling molecules to distant structures.
One key problem dealt with in this issue concerns the mechanisms by which
neurons, glia and gland cells give rise to extrasynaptic secretion. What are the similarities to and differences from the way in which secretion occurs from presynaptic
& 2015 The Author(s) Published by the Royal Society. All rights reserved.
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(a) Comparison of mechanisms for synaptic and
extrasynaptic exocytosis of serotonin, dopamine,
noradrenaline and peptides
Far less is known about extrasynaptic secretion than about
transmitter release by presynaptic nerve terminals or gland
cells. For example, the time course and magnitude of transmitter release have been measured with extraordinarily high
resolution in motoneuron terminals, thanks to the occurrence
of miniature endplate potentials and by the measurement of
ion currents that occur in the receptors of the postsynaptic
muscle membrane [15]. Thus, reliable estimates have been
made of the number of acetylcholine molecules in a small
(40–50 nm diameter) clear vesicle [16], the timing of calcium
in the presynaptic membrane [17], the molecular mechanisms
for docking and fusion [18,19] and the number of vesicles
that release transmitter per impulse [20].
A major advance is that one can observe presynaptic steps
in the release mechanism by electron microscopic tomography [21]. Thin sections of a presynaptic terminal at motor
nerve endings have been tilted through more than 708 to
allow three-dimensional reconstructions of terminals from
electron microscopy sections of intracellular and membrane
structures at subnanometre resolution, at rest or in response
to impulse activity. Electron tomography allows one to reconstruct the molecular steps by which synaptic vesicles move
towards, dock with the presynaptic plasma membrane and
become fused. Docking is a precondition for the vesicle
fusion with the presynaptic membrane and release of neurotransmitter into the synaptic cleft. Synaptic vesicles do not
dock just anywhere, but only at a specialized region known
as the ‘active zone’. The active zone consists of aggregates
of macromolecules that are attached to the cytosolic surface
of the presynaptic membrane and to calcium channels. The
highly ordered network of the active zone can be classified
by the position and associations of distinct groups of macromolecules. One type of structure is connected to calcium
channels in the presynaptic membrane close to the docked
synaptic vesicles. Before a vesicle becomes docked, it moves
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Phil. Trans. R. Soc. B 370: 20140181
2. Problems tackled by papers in this issue
towards the active zone. Membrane proteins of a vesicle that
will interact with the active zone material must arrive in a
characteristic arrangement determined by a radial assembly
of macromolecules. As a result, in response to electrical
stimulation, a specific region of the vesicle membrane—the
fusion domain—is brought into direct contact with the presynaptic membrane. Vesicle fusion incorporates a stereotyped
sequence of changes in the molecules of the active zone molecules and the vesicles. Open questions that remain bear on
the problem of identifying these proteins and understanding how a docked vesicle becomes primed for fusion and
transmitter release.
Release of transmitters and peptides from gland cells
follows a different scheme. Molecules are contained in large
(greater than 100 nm) electrondense vesicles [22]. Vesicle
fusion requires longer-lasting depolarization than that
required for release of synaptic clear vesicles [23]; in addition,
calcium entry occurs through different sets of channels [24].
In response to depolarization, electrondense vesicles in chromaffin cells are transported actively towards the plasma
membrane where they fuse to produce exocytosis [25].
There is evidence that the activation volume of fusion complexes regulates the kinetics of exocytosis and therefore, the
probability of its fusion with the plasma membrane. The
role of the activation volume has been studied by applying
hydrostatic pressure to chromaffin cells (see [26]). The reaction
and equilibrium kinetics of secretion have been measured as
capacitance changes by use of the patch clamp technique.
When pressures of up to 20 MPa (200 Atm) are presented, the
changes in the kinetics of exocytosis can be explained in
terms of interactions between the vesicles and proteins that
cause exocytosis. The results indicate a similar activation
volume of 390 + 57 Å3 for large dense core vesicle fusion in
chromaffin cells; the value is similar for the degranulation of
mast cells. This information predicts protein conformational
changes during the reactions involved in vesicle fusion.
Extrasynaptic release of transmitters and peptides occurs
in animals as different as leeches and mammals. Trains of
impulses are required and exocytosis is maintained for long
periods. Extrasynaptic release is accomplished differently
from release at motorneuron terminals. Detailed studies of
the steps between electrical activity and exocytosis have
been made in central neurons releasing serotonin or oxytocin
and vasopressin. Serotonin (5-hydroxy tryptamine, 5-HT) is
an important transmitter in the central nervous systems of
vertebrates and invertebrates, where it contributes to the
modulation of multiple functions from development to disease. Malfunction of the serotonergic system may cause
sudden death and many antidepressants act on its reuptake
after release. Serotonin release from nerve terminals resembles
that occurring at neuromuscular presynaptic terminals [27].
However, serotonin is also released from extrasynaptic sites,
such as cell bodies and dendrites. Extrasynaptic release of
serotonin has been studied by structural and physiological
experiments made on cell bodies of Retzius neurons in the
central nervous system of the leech (see [28]). The large
80 mm diameter soma of a Retzius neuron contains numerous
clusters of electrondense vesicles filled with serotonin. Electrical stimulation of the soma causes electrondense vesicles to
move en masse to the cell surface without docking at an identifiable active zone. There they fuse and release serotonin for
several minutes. Vesicle transport and release depend on
the frequency of electrical stimulation. Unlike the serotonin
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nerve terminals? In conventional synapses, transmission is fast,
and the transmitter acts for milliseconds to seconds on post- and
also presynaptic targets [1,8]. At presynaptic nerve terminals
short-term plasticity lasting for seconds, minutes or hours is evident as facilitation, depression and post-tetanic potentiation of
release [9,10]. By contrast, long-term changes in the efficacy of
transmission are caused for the most part by postsynaptic
mechanisms, involving NMDA [11] and metabotropic receptors [12,13]. Release from neuronal cell bodies and dendrites
gives rise to maintained transmitter concentrations in the extracellular spaces of not only near, but also distant neurons, glial
cells and blood vessels [14]. Accordingly, a second major objective of papers presented here was to analyse how extrasynaptic
release can influence integrative functions of the nervous
system, behaviour and disease. Examples are provided by
long-term effects of transmission, (i) on integrative mechanisms
in the central nervous system, (ii) on glial regulation of blood
flow through the brain, and (iii) on motor performance in
patients with Parkinson’s disease and on higher functions of
the brain.
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(b) Glia and extrasynaptic release
One of the first physiological properties of neuroglial cells to
be defined was their coupling by electrical synapses [34]: the
spread of current, ions and molecules from glial cell to glial
cell allows glia to act as a sheet rather than as individuals.
The subsequent discovery of propagated calcium waves
added a new dimension to ideas about their functions in
relation to those of neurons. Well-established functions of
glial cells that have been known for some time are the formation of myelin, the guidance of axons during development
and the formation of the blood–brain barrier. Papers cited
in this section are concerned with the question of how calcium waves arise, what are their functional properties, what
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Phil. Trans. R. Soc. B 370: 20140181
electrondense vesicles in dendrites and priming enhances
activity-dependent release of oxytocin and vasopressin. This
provides a feedforward mechanism that lasts tens of minutes.
One can speculate that oxytocin and vasopressin act as
hormone-like signals on distant brain targets. The slow prolonged action on specific peptide receptors has been shown
to trigger a temporary functional reorganization of neuronal
networks and thereby induce prolonged changes in behaviour.
The previous paragraphs have shown that neurons of vertebrates and invertebrates that release serotonin, dopamine or
peptide hormones share similar mechanisms for exocytosis
from their soma and dendrites. Open questions that remain
concern the sites at which dense cored vesicles become
docked on the membrane and the final steps and molecules
that lead to fusion. A principal point of convergence between
release at synaptic terminals and extrasynaptic release is the
essential role of calcium.
The mechanisms for extrasynaptic exocytosis described
above occur in the absence of closely apposed postsynaptic
counterparts. Moreover, the lack of correlation between the
release sites and the receptor localization has suggested that
signalling molecules must reach their receptors via ‘volume
transmission’ (see [32]). In addition, there is now evidence
that signalling molecules can reach their targets by the extracellular movement of vesicles released from neurons and glia
through extracellular space [32]. Those vesicles can transfer
lipids and proteins, including receptors, and GTPases, as
well as subsets of mRNAs and non-coding regulatory
micro-RNAs, to other cells located distantly. Such transport
offers opportunities for long-term modulation of synaptic
transmission and also for prion infection and mobilization
of proteins that contribute to Alzheimer’s disease. Another
new area of research has shown that the formation of heterodymeric receptors adds complexity to the number of possible
responses to a given transmitter molecule.
In this regard, catecholamines are released from the cell
bodies of superior cervical ganglion neurons and from chromaffin cells in response to activation of nicotinic acetylcholine
receptors. This release is activated by calcium entry across the
pore of the acetylcholine receptor [33]. However, in both cell
types, activation of muscarinic acetylcholine receptors
reduces the mean open time of the nicotininc receptor pore.
The effect of the muscarinic agonist requires time and acts
to reduce the amount of calcium entry in response to delayed
activations of the acetylcholine receptor. By doing this, activation of muscarinic receptors blocks exocytosis. The effect
is mediated by G proteins with contributions of protein
kinases A and C.
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release that occurs at synaptic terminals, single action potentials or trains at 1 Hz fail to evoke transport of vesicles to the
cell membrane. By contrast, following trains of stimuli at
20 Hz, about 100 vesicle clusters move to different places
on the plasma membrane, where they fuse. The exocytosis
in which tens of thousands of vesicles release serotonin
over periods of minutes is owing to a chain of intracellular
events triggered by calcium entry. This in turn causes a
wave of calcium-induced calcium release that seems to promote
adenosine triphosphate (ATP) synthesis by mitochondria. ATP
induces vesicle transport through kinesin motors coupled to
microtubules. Serotonin that has been released acts on autoreceptors; these induce an IP3-dependent calcium increase
in the soma, which produces further exocytosis. Thus, a positive feedback mechanism maintains exocytosis until the last
vesicles in each cluster fuse and the calcium levels return to
basal levels. Serotonin released from the soma acts on
surrounding glial cells, which take it up and presumably transport it to other sites of the nervous system. Records of the
electrical activity of neurons in the central nervous system of
the leech show that stimulation of a Retzius cell can produce
effects that last for several hours. Several lines of evidence
show that extrasynaptic release of serotonin modulates the
behaviour of the animal for prolonged periods [29].
Dopamine is another transmitter that is released extrasynaptically. It plays a key role in motor and emotive
pathways of the mammalian brain. Dysfunction of dopaminergic systems has been implicated in disorders that include
Parkinson’s disease, addiction and schizophrenia. In addition
to exhibiting classical vesicular release of dopamine from
their axon terminals, dopamine-containing midbrain neurons
release the transmitter from their cell bodies and dendrites
[30]. Axons of dopaminergic neurons in the brainstem project
to the dorsal and ventral striatum and to the forebrain. Extrasynaptic release of dopamine is also calcium-dependent,
although aspects of this dependence are not yet understood.
The dopamine that has been released activates D2 autoreceptors in dopaminergic neurons themselves. This activates
G-protein-coupled inwardly rectifying potassium channels.
Therefore, the local increases in the extracellular dopamine
concentration inhibit firing of the dopamine neurons. This
local autoinhibition helps to determine the pattern of dopamine
signalling at distant axonal release sites. Somatodendritic dopamine release also acts via volume transmission to modulate
transmitter release and activity of other midbrain neurons.
Hence, extrasynaptic release is a pivotal intrinsic feature
of dopaminergic neurons that can play a part in our understanding of physiology, higher functions of the brain and its
pathologies.
As with serotonin, the activity requirements for somatodendritic release of the neuropeptides vasopressin and
oxytocin are distinct from those for release by nerve terminals
[31]. Thus, as expected, large electrondense vesicles in axonal
terminals of the magnocellular neurons of the hypothalamic
supraoptic nucleus and paraventricular nucleus fuse with
high reliability following individual action potentials. By contrast, the fusion of electrondense vesicles in the soma requires
sustained calcium elevation; the actual fusion events are not
locked to cell firing. The process is slower than synaptic
release and depends on trains of impulses. Moreover, exocytosis in the dendrites can be evoked by calcium release from
intracellular stores without any depolarization. Intracellular
calcium release promotes ‘priming’ of the releasable pool of
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The papers cited in this section show different ways in which
transmitters liberated from extrasynaptic sites can have profound and long-lasting effects on integrative mechanisms of
the nervous system. These examples include interactions
between neurons, glial cells and blood vessels.
At the cellular level, two different transmitters released
extrasynaptically have opposite effects on the dendritic spiking
of cortical neurons. Glutamate and ATP released extrasynaptically, most probably by glial cells, have been implicated in the
regulation of the properties of dendritic spikes [37]. These
spikes are produced upon activation of presynaptic inputs
onto the dendrites. A combination of calcium imaging, synaptic stimulation, glutamate or adenosine iontophoresis and
specific pharmacological agents that act on the NMDA and
A1 adenosine receptors, has shown that the activation of extrasynaptic NMDA receptors increases the amplitude and
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Phil. Trans. R. Soc. B 370: 20140181
(c) Effects of extrasynaptic transmission on functional
activity of the central nervous system
duration of dendritic spikes. These effects are produced
through the activation of NR2C/D receptors that increases
the duration of calcium influx. By contrast, the activation of
extrasynaptic A1 adenosine receptors reduces the duration
of the spikes via the activation of a slow-activating potassium
current. The results suggest that the release of glutamate and
ATP from unknown cells, probably glia, contributes to
initiation, maintenance and termination of local dendritic glutamate-mediated regenerative potentials and the associated
local calcium influx.
The retina has provided examples that show how extrasynaptic release influences functional integration. A clear
example is the importance of dopamine release for visual
perception. Certain retinal amacrine cells synthesize both
dopamine and GABA (here called ‘dopaminergic amacrine
cells’). Both transmitters are secreted extrasynaptically by
exocytosis over the cell surface and act on neighbouring
and distant neurons by volume transmission [38]. That dopamine and GABA are co-released from cell bodies was shown
by measuring their release from the soma of individual
amacrine cells isolated from the mouse retina: a proportion
of the events of dopamine and GABA exocytosis occur
simultaneously. In the retina, dopaminergic amacrine cells
establish GABAergic synapses onto the ‘AII’ amacrine cells,
which transfer rod signals to cone bipolar cells. GABAA
receptors are clustered at postsynaptic terminals of the AII
neurons, but dopamine receptors are not. This shows that
dopamine released from synaptic terminals or extrasynaptically acts on receptors that are diffusely distributed over the
surface of postsynaptic targets. The functions of dopaminergic
amacrine cells are complex because of the simultaneous
release of GABA as well as dopamine. Dopamine is released
upon illumination; it acts through volume transmission on
many types of retinal neurons and sets their gain for vision
in bright light. It seems likely that GABA released by the
same dopaminergic amacrine cells at their synaptic terminals
blocks signals from rods that have been suddenly exposed to
bright illumination. In this way, GABA would prevent the
rods from entering the cone pathway and would improve
the signal-to-noise ratio of colour vision. A further possibility
is that extrasynaptic release of GABA by dopaminergic amacrine cells could give rise to a ‘GABAergic tone’. Maintenance
of a GABA concentration in the intercellular spaces may
counteract the effects of the spillover of glutamate molecules
from photoreceptor synapses and prevent crosstalk between
OFF- and ON-pathways in the crowded environment of the
inner plexiform layer.
The effects of extrasynaptic transmission go beyond the
regulation of electrical responses of neurons; they also
include the regulation of the activity of glia, blood vessels
and muscle. Activity of nerve cells, irrespective of their transmitters, depolarizes glial cells, which in turn generate a local
increase in blood flow just where it is most needed. Again, in
the retina, ganglion cells, which provide the output from the
retina, are inhibited by the release of ATP from Müller cells,
the main type of retinal glial cell [39]. Of particular interest
is that retinal glial cells release vasoactive agents as well as
ATP. These serve to regulate local blood flow to the central nervous system, directing it to regions of electrical activity. Thus,
calcium signals in glial cells cause the release of vasoactive
metabolites of arachidonic acid (including prostaglandin E2
and epoxyeicosatrienoic acids) that dilate retinal blood vessels.
This accounts for the phenomenon that stimulation of the
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molecules do glial cells secrete and the role these molecules
play in the functioning of the nervous system.
ATP is a transmitter molecule that is extrasynaptically
secreted by neurons and glia [35]. Extracellular ATP serves as
a signal for diverse physiological functions, some mediated
by spread of calcium waves between astrocytes. In addition,
ATP release from glia occurs through the Pannexin1 channel.
This is a non-junctional membrane channel with a large conductance (500 pS) and unselective permeability to molecules
of less than 1.5 kDa. The interaction between Pannexin 1 and
ATP is intimate. The channel serves as the conduit for ATP
efflux from cells along its concentration gradient. Control of
ATP efflux is provided by ATP via two opposite effects. The
Pannexin 1 channel itself is modulated by ATP through activation of ionotropic P2X receptors or metabotropic P2Y
receptors. Hence, activation of an ATP release channel by
ATP represents another positive feedback loop. This would
lead to cell death in the absence of a control mechanism,
because purinergic receptors are linked to apoptotic processes. However, the direct binding of ATP to the Pannexin1
protein prevents this death through closure of the channel.
Extracellular ATP produces calcium waves on neighbouring glial cells. ATP released from stimulated glial cells
activates P2Y receptors, resulting in calcium release from
internal stores. The calcium waves produced in this way
flow from one glial cell to another through gap junctions.
Calcium waves in glial cells are also generated by hydrogen
peroxide, a reactive oxygen species present in glial cells.
The propagation of calcium waves in hippocampal astrocytes
is blocked by scavengers of reactive oxygen species.
Other molecules secreted by glial cells are growth factors.
Exposure of glial cells to thyroid hormone causes them to
release basic fibroblast growth factor and neurotrophin-3 [36].
These proteins increase the density of sodium currents in cultured hippocampal neurons. Similar increases in sodium
current are produced by activated microglial cells and by
tumour necrosis factor. Together, these findings suggest that
release of growth factors from satellite cells can alter neuronal
excitability over a time course of several days. It seems possible
that growth factors secreted by glia might account for changes
in neuronal excitability that occur in conditions of thyroid hormone imbalance. Important effects of extrasynaptic release of
signalling molecules by glia are further considered in §2c.
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In Parkinson’s disease, the loss of dopaminergic neurons
of the substantia nigra compacta causes the development of
distinctive a-synuclein (a-syn) inclusions in nigrostriatal projections, in addition to decreasing the concentration of
dopamine in the striatum [41]. The a-syn inclusions can
serve as a pathological measure of the severity of the disease.
New evidence suggests that the a-syn inclusions play a role
in synaptic transmission and in the physiological actions
of dopaminergic neurons. In toxic and transgenic a-syn
models of Parkinson’s disease, studies have been made of
the effect of various levels of dopamine denervation on
synaptic plasticity in striatal neurons and interneurons. An
intriguing hypothesis is that dyskinesias following treatment
might arise from alterations in long-term potentiation. In
experimental Parkinson’s disease, the dyskinesias are correlated with changes in the reversal of long-term potentiation.
Another example of extrasynaptic release that bears on Parkinson’s disease and dyskinesias is that of nitric oxide (NO). As
a gas, NO is not released by exocytosis. Instead, it diffuses out
of the cells that produce it to activate neighbouring targets via
volume transmission. A prominent disorder in patients suffering from Parkinson’s disease is a dyskinesia that arises as a
consequence of treatment by L-DOPA. The mechanism for
the production of the uncoordinated, involuntary, movements
that follow long-term treatment with L-DOPA are not yet fully
understood. New evidence [42] suggests that extrasynaptic
release of NO plays a part. The gas is synthesized by NO
synthase (NOS), which is co-localized with the enzyme responsible for the production of dopamine in cell bodies of the
nigrostriatal pathway. In the mouse, inhibition of NOS blocks
dyskinesia that follows treatment with L-DOPA. Clinical
trials are now in progress to test whether blockage of NO synthesis can alleviate dyskinesia in patients suffering from
Parkinson’s disease who are being treated with L-DOPA.
Small soluble oligomers of amyloidogenic proteins have
been implicated in Alzheimer’s and Parkinson’s diseases [43].
However, the pathway leading to toxicity remains obscure.
Most of the mechanisms that have been proposed are generic
in nature, and they do not directly explain the neuron-typespecific lesions observed in many of these diseases. For
example, dysfunction of cholinergic and serotonergic cells is
prominent in the initial stage of Alzheimer’s disease, whereas
dopaminergic cells are lost in Parkinson’s disease. New evidence indicates that components of the neurotransmitter
vesicular machinery are indeed intermediaries in the process
of amyloid-induced toxicity. The toxic oligomers may act on
the neurotransmitter synaptic release machinery: vesicular traffic, size of the storage and recycling vesicle pools, endocytosis
and vesicular content. Direct multiphoton imaging of serotonin
(e) Concluding remarks
This collection of papers points the way for the generation of
new data and hypotheses for the mechanisms and significance of an essential form of signalling in the nervous
system, namely the release of chemical transmitters and
other key molecules from cell bodies, dendrites and axons
of neurons, and from glial cells. At first glance, the principal
differences from synaptic transmission are the slower time
course and wider distribution of targets. However, the
detailed cellular studies shown here demonstrate that multiple steps must be accomplished for electrical stimulation
to evoke somatic or dendritic exocytosis. Each of these steps
is a potential regulatory mechanism. An important feature
of this regulation is that the extracellular concentrations of
the signalling molecules modulate neuronal functions at
many levels, from channel populations to higher integrative
functions such as mood states and diseases. In addition to
the signalling molecules discussed here, many others act
extrasynaptically. It is therefore not surprising that more
than one and maybe many signalling molecules act simultaneously on the same target cell. This suggests that the
enormous complexity and diversity of responses of the nervous system to a given stimulus may be part of a large
catalogue of potential responses. The list of extrasynaptic
mechanisms provided in this issue of Philosophical Transactions is incomplete and one can expect new surprises. An
unexpected finding has been made at sensory nerve endings.
In muscle spindles the sensory nerve endings release glutamate, which acts back on the nerve terminals to raise their
electrical excitability during a stretch [44,45].
It is a sobering thought that knowledge of the circuitry of
the brain will probably not on its own explain how it works.
For example, without knowing the detailed connections of
the cells in the retina, one cannot begin to guess how light
is transduced to give rise to action potentials in the optic
nerve. But the anatomy on its own, and even the properties
of the synapses, do not reveal the essential role of extrasynatptically released dopamine in the retina or in other areas
of the nervous system.
A further comparison is between extrasynaptic release
and glandular secretion. This comparison contributes to our
knowledge of basic mechanisms of communication; it also contributes to our understanding of how three complementary
communication systems act in concert to regulate integrated
physiology. Fast synaptic transmission allows rapid responses
or long-term changes in efficacy. In parallel, extrasynaptic
exocytosis modulates such responses over intermediate- and
long-term periods, and the endocrine system links the nervous
system to the rest of the body. Another player in extrasynaptic
exocytosis is glia. By capturing and releasing transmitters and
other molecules, glial cells link the electrical activity of neurons
with the physiology of other cell types in the nervous system.
However, the mechanism by which glia direct and release
transmitters onto their targets is still poorly understood.
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Phil. Trans. R. Soc. B 370: 20140181
(d) Extrasynaptic transmitter release and disease
and dopamine has been used to measure quantitatively the effect
of the toxic amyloids on the intracellular vesicles. These studies
could provide a connection to the neuron-type specificity
observed in the neurodegenerative diseases. The vesicular
machinery provides both a new assay for monitoring disease
progression, and a new target for developing pharmacological
agents for treating diseases of the nervous system.
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retina with flickering light causes retinal blood vessels to dilate,
resulting in a local increase in blood flow. In addition, tonic
release of ATP from retinal glial cells stimulates P2X1 receptors
on vascular smooth muscle cells. Tonic activation of these
muscle cells is principally responsible for generating tone in
retinal blood vessels. Therefore, activity of nerve cells, irrespective of their transmitters, depolarizes glial cells (by potassium
liberation), which in turn generates a local increase in blood
flow just where it is most needed. A function for glial cells
that had been suggested many years ago [40] has now been
shown to be of crucial importance.
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It is one of the ironies of science that the first inklings of
chemically mediated synaptic transmission were postulated
(at a time when all synaptic transmission was supposed to be
electrical in nature) through studies of the release of adrenaline
by the adrenal medulla and of acetylcholine from the vagus
nerve to the heart. Both constitute extrasynaptic release.
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rstb.royalsocietypublishing.org
Hence, the physiological effects of extrasynaptic transmission
contribute to regulate the responses of neural circuits directly
by changing the neuronal and glial properties; they also influence the energy and oxygen availability through the regulation
of blood flow. It is therefore not surprising that dysfunctions of
extrasynaptic release may contribute to different diseases.
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