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Electrical synapses and their
functional interactions with chemical
synapses
Alberto E. Pereda
Abstract | Brain function relies on the ability of neurons to communicate with each other.
Interneuronal communication primarily takes place at synapses, where information from one
neuron is rapidly conveyed to a second neuron. There are two main modalities of synaptic
transmission: chemical and electrical. Far from functioning independently and serving
unrelated functions, mounting evidence indicates that these two modalities of synaptic
transmission closely interact, both during development and in the adult brain. Rather than
conceiving synaptic transmission as either chemical or electrical, this article emphasizes the
notion that synaptic transmission is both chemical and electrical, and that interactions
between these two forms of interneuronal communication might be required for normal
brain development and function.
Dominick P. Purpura
Department of Neuroscience,
Albert Einstein College of
Medicine, 1300 Morris Park
Avenue, Bronx,
New York 10461, USA.
e‑mail: alberto.pereda@
einstein.yu.edu
doi:10.1038/nrn3708
Published online
12 March 2014
Communication between neurons is required for
brain function, and the quality of such communication enables hardwired neural networks to act in a
dynamic fashion. Functional interactions between
neurons occur at anatomically identifiable cellular
regions called synapses. Although the nature of synaptic
transmission has been an area of enormous controversy
(BOX 1), two main modalities of synaptic transmission —
namely, chemical and electrical — are now recognized. At
chemical synapses, information is transferred through
the release of a neurotransmitter from one neuron
and detection of the neurotransmitter by an adjacent
cell1, whereas in electrical synapses, the cytoplasm
of adjacent cells is directly connected by clusters of
intercellular channels called gap junctions2. Although
cellular specializations for both forms of transmission can be found at various neuronal sites (dendrites,
somata and axons), chemical transmission normally
occurs between synaptic terminals from axons and
the dendrite or soma of a second neuron, muscle fibre
or gland cell. The presence of these two modalities of
synaptic transmission does not exclude the possibility
that brain cells could also communicate by alternative mechanisms, such as volume transmission (diffusion of neurotransmitters through the extracellular
space to reach remote target cells)3 and the generation
of electrical fields that are capable of influencing the
excitability of nearby neurons4.
Electrical and chemical synapses are now known to
coexist in most organisms and brain structures, but details
of the properties and distribution of these two modalities of
transmission are still emerging. Most research efforts
have focused on exploring the mechanisms of chemical transmission, and considerably less is known
about those underlying electrical transmission. It was
thought that electrical synapses were more abundant
in invertebrates and cold-blooded vertebrates than
in mammals. However, a wealth of data now indicate
that electrical synapses are widely distributed in the
mammalian brain5. In addition to the retina, inferior
olive and olfactory bulb, structures in which electrical transmission has been known to occur for some
time5, electrical synapses have been found in disparate regions of the mammalian CNS and have been
shown to constitute a distinct phenotypic feature
of inhibitory interneurons in general6–8.
Perhaps because the appreciation of each form of
synaptic transmission occurred in a sequential manner
(at least in mammals), there is a widespread notion that
electrical and chemical synapses operate independently.
This article reviews the evidence that chemical and electrical synapses functionally interact during development
and in adulthood. Rather than being a comprehensive
review of the experimental evidence, the focus here
is on a few examples that highlight such functional
interactions.
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Box 1 | The debate over the nature of synaptic transmission
S. Ramón y Cajal and C. Sherrington, the fathers of modern neuroscience, established
that networks of multiple elementary units, called ‘neurons’, communicate with each
other through functional specializations called ‘synapses’. Their seminal contributions
were followed by a bitter debate over the nature of synaptic transmission: was it
mediated by chemical or electrical signals? This controversy was known as ‘The War of
the Soup and the Sparks’ (REF. 170). Although several researchers, most notably T. R.
Elliott171 and later O. Loewi172, demonstrated the existence of neurotransmitters with
actions on postsynaptic cells, there was still controversy over whether transmitter
release could occur in a fraction of a millisecond, the synaptic ‘delay’ indirectly
measured by Sherrington173. B. Katz and colleagues174 demonstrated that synaptic
transmission at the frog neuromuscular junction was an electrically mediated,
calcium-dependent form of transmitter release, which occurred within a fraction of a
millisecond. Transmission by such a mechanism was also shown to occur in the CNS,
leading to a general agreement that synaptic transmission was chemically mediated.
However, in 1958, D. Potter communicated at a ‘Monday night fight’ of the Marine
Biological Laboratory in Woods Hole (USA) (so called because of the contentious nature
of the scientific exchanges) the striking properties of synaptic transmission in crayfish,
which challenged all the criteria established for chemical transmission. Postsynaptic
signals reproduced the time course of presynaptic signals, and transmission was
bidirectional and, surprisingly, voltage-dependent. The findings provided the earliest
evidence in support of the existence of electrical synaptic transmission175 and were
soon followed by seminal studies in the teleost brain by M. V. L. Bennett and
colleagues176, J. D. Robertson and colleagues177 and E. J. Furshpan178, in which
physiological and ultrastructural analyses were combined. Their search for the
anatomical basis of electrical transmission greatly contributed to the identification of
the cellular structures that we know today as gap junctions. The more recent
demonstration of the ubiquitous presence of electrical synapses in the mammalian
brain led to the indisputable conclusion that chemical transmission and electrical
transmission coexist in all nervous systems.
Lateral excitation
The ability of an excited neuron
(or sensory afferent) to excite
its neighbours. Although it
reduces discrimination, lateral
excitation greatly enhances
input sensitivity. It is a
less-appreciated property of
sensory and cortical networks.
Are chemical synapses more sophisticated?
Chemical versus electrical synapses. From an evolutionary point of view, chemical communication between cells
preceded electrical communication9. Communication
with chemical signals occurs in unicellular organisms
such as bacteria10, in which it mediates important phenomena such as quorum sensing 11 (the mechanism
underlying the detection of bacterial population density). More-specific communication between individual
cells requires complex cellular specializations between
the interacting partners. The presence of such cellular
specializations is not exclusive to neurons and is a characteristic that neuronal chemical and electrical synapses
share with immunological synapses between a lymphocyte and an antigen-presenting cell12, which dynamically
form to facilitate the transfer of information between
these two cells. Chemical transmission requires sophisticated presynaptic molecular machinery that regulates
neurotransmitter release in a probabilistic manner
when an action potential invades the synaptic terminal1
(although at some contacts, release can also be proportional to changes in resting membrane potential13). Such
transmission also requires a similarly complex postsynaptic molecular machinery, including ionotropic
(ligand-gated ion channels) and metabotropic receptors
(G protein-coupled receptors that act indirectly through
a secondary messenger) (FIG. 1a), which are capable of
detecting and translating messages into various postsynaptic events, ranging from changes in resting potential
(‘synaptic potential’) to gene expression1. These features
enable chemical synapses to adapt to diverse functional
requirements. The mechanisms and general properties
of chemical synaptic transmission have been extensively
reviewed (see REF. 1 for a review).
Electrical transmission between neurons is mediated by gap junctions2, which are clusters of intercellular channels that directly connect the interiors of two
adjacent cells (FIG. 1b), enabling the bidirectional passage
of electrical currents and small molecules (for example,
calcium, cyclic AMP and inositol-1,4,5‑trisphosphate).
Gap junction channels are formed by the docking of two
hexameric connexin ‘hemichannels’ (also called ‘connexons’); that is, one from each adjacent cell14. Strikingly,
although they assemble into almost identical structures,
connexons in invertebrates and vertebrates are formed
by two different multigene families of proteins: namely,
connexins, which are unique to chordates, and a second family including innexins and pannexins, which are
found in invertebrates, prechordates and chordates2,14
(note that in contrast to innexins, pannexins do not
seem to form intercellular channels in tissues and thus
are thought to operate only as unpaired hemichannels in
vertebrates15). Such evolutionary convergence highlights
the functional importance of gap junction intercellular
communication.
From a family of over 20 genes in mammals14, only a
handful of connexins have been found to be expressed
in vertebrate neurons, including connexin 36 (CX36; also
known as GJD2), CX45 (also known as GJC1), CX50
(also known as GJA8), CX30.2 (also known as GJC3)
and CX31.1 (also known as GJB5) (see REFS 16–18 for
reviews). To date, the retina is the neuronal tissue in
which the diversity of neuronal connexins has been most
investigated (see REF. 19 for a review). Because of its widespread distribution, CX36 is considered to be the main
‘synaptic’ connexin in the mammalian brain20. However,
although electrical transmission is dramatically reduced
in CX36‑knockout mice, some level of electrical and
tracer coupling can be detected in these animals21,22, suggesting that synaptic gap junctions may be composed
of additional connexins. Several of the 25 members of
the innexin family have been identified in invertebrate
neurons, mainly in fly 23, leech24 and worm neurons25.
Although electrical synapses can act, to some extent,
in a metabotropic manner by allowing the passage of
small metabolites (a critical property of electrical synapses during development; see below), they, unlike
chemical synapses, lack the ability to amplify and
transform presynaptic signals. However, this does not
mean that electrical synapses are less sophisticated;
their sophistication just relies on a different functional
property — their bidirectionality — which enables them
to coordinate the activity of large groups of interconnected neurons2. Based on this bidirectional and analogical (that is, they do not require an action potential)
nature, electrical synapses are particularly efficient at
detecting the coincidence of simultaneous subthreshold depolarizations within a group of coupled neurons,
a phenomenon that increases neuronal excitability and
promotes synchronous firing 22,26–29. Electrical synapses
are also highly effective at mediating lateral excitation
and increasing the sensitivity of sensory systems, as it
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a Chemical synapse
b Electrical synapse
Action
potential
Ca2+
Action
potential
Presynaptic
terminal
Synaptic
vesicle
Gap junction
channel
Neurotransmitter
Ionotropic
receptor
Metabotropic
receptor
Membrane
potential
Postsynaptic
terminal
Gene
expression
Coupling
potential
Biochemical
cascades
Figure 1 | The two main modalities of synaptic transmission. a | Chemical transmission requires sophisticated
Nature Reviews
| Neuroscience
presynaptic molecular machinery that regulates neurotransmitter release in a probabilistic
manner upon
depolarization of the presynaptic terminal — in this case, by the arrival of an action potential — which leads to the
activation of voltage-gated calcium channels (VGCCs). Similarly complex postsynaptic molecular machinery is also
required. This includes the presence of ionotropic and metabotropic receptors that are capable of detecting and
translating the presynaptic message (neurotransmitters) into various postsynaptic events, ranging from changes in
resting membrane potential to gene expression, thus amplifying the presynaptic signal. b | Electrical transmission is
mediated by clusters of intercellular channels called gap junctions that connect the interior of two adjacent cells, and
thereby directly enable the bidirectional passage of electrical currents carried by ions (arrows) as well as intracellular
messengers and small metabolites (not illustrated here). Electrical synapses are bidirectional in nature: when a
presynaptic action potential propagates to the postsynaptic cell, the membrane resting potential of the postsynaptic
cell simultaneously propagates to the presynaptic cell.
Escape networks
Neural networks found in
invertebrate and vertebrate
nervous systems (usually
containing a small number of
cells that include sensory and
motor neurons) that seem
optimized to mediate fast
escape behaviours.
Mauthner cell
A large reticulospinal neuron
found in teleost fish that
mediates (among other
functions) tail-flip
sensory-evoked escape
responses.
occurs in the retina30 and the primary afferents of escape
networks31–33. Gap junction-mediated lateral excitation
has also been shown to occur in a network of cerebellar
interneurons, promoting the spread of chemically mediated synaptic inputs between remote dendritic arborizations34. Because of their reliability (transmission at
electrical synapses is not probabilistic in nature) and the
absence of a synaptic delay (transmission occurs instantaneously), electrical synapses are also a typical feature
of escape response networks in both invertebrates33,35,36
and vertebrates37.
Together, these findings indicate that, from a functional point of view, no particular form of transmission
is ‘better’ than the other one. Rather, the mechanisms of
chemical and electrical transmission seem to be specifically adapted to communicate different aspects of cellular
processing and functioning.
Structural complexity of electrical synapses. Bolstered by
the implicit molecular complexity of chemical transmission and its ability to undergo plasticity, there was until
recently the widespread notion that electrical transmission is a rather simple, static and rigid form of neuronal
communication. However, studies in cell expression
systems38–43 and in neurons44 have shown that gap junctions are highly dynamic, complex structures and that
their channels are actively turned over. More specifically,
ultrastructural and functional analysis of mixed (electrical
and chemical) synapses on the goldfish Mauthner cell (a
large reticulospinal neuron in fish37,45) revealed that — as
observed at gap junctions formed by recombinant CX43
in cell expression systems43 — gap junction hemichannels are simultaneously added at the edges of gap junction
plaques (clusters of intercellular gap junction channels),
where they dock with hemichannels in the apposed membrane to form cell–cell channels, and that intact junctional
regions are removed from the centre of these plaques into
either the presynaptic axon or the postsynaptic Mauthner
cell dendrite44. Moreover, in this study, electrical coupling
was readily modified by peptides that interfere with
endocytosis or exocytosis, suggesting that the strength
of electrical synapses at these terminals is determined,
at least in part, by a fast turnover of gap junction channels44. Indeed, the half-life of this turnover was estimated
to be 1–3 hours44, a time consistent with that observed
for other ion channels and synaptic receptors46, indicating
that this dynamic process could be involved in regulating electrical transmission (FIG. 2). Thus, as it occurs with
postsynaptic receptors at glutamatergic chemical synapses
for the regulation of their synaptic strength47–51, regulated
trafficking of hemichannels and intercellular channels
could underlie modifications of gap junctional conductance. Furthermore, like their chemical counterparts,
electrical synapses are highly modifiable by the action
of neuromodulators such as dopamine and are capable of
activity-dependent plasticity (see REF. 52 for a review).
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Postsynaptic density
(PSD). Originally named after
its identification by electron
microscopy, the term refers to
a macromolecular complex
that supports postsynaptic
function at chemical synapses
and includes neurotransmitters
receptors, scaffolding proteins
and regulatory signalling
molecules.
PSD95
(Postsynaptic density
protein 95). A protein that
contains multiple domains that
mediate its association with
receptors, cell-adhesion
molecules and cytoplasmic
signalling molecules. By virtue
of these interactions, it
influences the surface delivery,
stability and subcellular
location of postsynaptic
receptors, and facilitates their
functional coupling to
downstream signalling
pathways.
The existence of such dynamic structural and functional properties indicates that electrical transmission
must rely on more than the intercellular channels.
Constitutive trafficking and regulated trafficking of
ligand-gated ion channels to and from the plasma membrane are important processes for the maintenance of
chemical synaptic function. At glutamatergic synapses,
this requires interactions between the glutamate receptors’ carboxyl termini and various cytosolic proteins
and scaffolding proteins50,53,54, which are mostly located
at the postsynaptic density (PSD)55 (FIG. 2a). Similarly,
electrical synapses require the molecular machinery
to mediate the turnover of gap junction channels. Gap
junctions are now considered to be a part of multiprotein complexes51–53. Electron-dense areas similar to those
of PSDs, referred to as ‘semi-dense cytoplasmic matrices’ (REF. 56), have been observed at neuronal gap junctions when explored by electron microscopy (FIG. 2b).
The detailed composition of these PSD-like structures
is largely unknown57, although several molecules are
known to interact with CX36 (REFS 58–61) and its teleost
homologue62, most notably zonula occludens protein 1
(ZO1)59,60,62 and calcium/calmodulin-dependent protein kinase II (CaMKII)63,64. ZO1 is a scaffolding protein
of the MAGUK family that is known to associate with
many connexins65, and it might have a similar role in
neuronal gap junctions to that of PSD95 at glutamatergic synapses. Conserved regions of the C terminus of
CX36 (and its two teleost homologues)61,62,66 mediate its
interactions with ZO1 and are required for the insertion
of new gap junction proteins into electrical synapses44,66.
ZO1 has also been proposed to have an essential role
a Chemical synapse
in regulating the transition from connexon to intercellular gap junction channel formation in the periphery
of CX43‑containing junctions67. In contrast to the
permanent structural role of ZO1, CaMKII has been
proposed to be a non-obligatory component of electrical synapses, with its association being linked to
synaptic activity (see below)64. Associated regulatory
proteins seem to be crucial for innexin-based electrical
transmission too, as a stomatin-like protein (UNC‑1)
was shown to be required for proper channel function
at gap junctions formed by UNC‑9 (an innexin) in
Caenorhabditis elegans68,69.
Recent data suggest that, similarly to pre- and
postsynaptic sites at chemical synapses, one side of an
electrical synapse should not necessarily be considered to be the mirror image of the other 70. Molecular
asymmetries in neuronal gap junctions suggest that
electrical synapses are functionally diverse. The intercellular channels at electrical synapses can in some
cases be constructed by the apposition of two different connexins, forming ‘heterotypic’ (as opposed to
‘homotypic’) gap junctions14. Gap junctions at auditory mixed synapses of the goldfish Mauthner cell are
constructed by the apposition of hemichannels formed
by two homologues of mammalian CX36 (CX35 and
CX34.7)70; whereas CX35 was restricted to presynaptic
hemiplaques, CX34.7 was found only in postsynaptic
hemiplaques, and together they formed heterotypic
junctions70. Heterotypic gap junction channels have
been associated with rectification of electrical transmission70–73, which is defined as the propensity of some
electrical synapses to display differential resistance to
b Electrical synapse
Hemichannel
insertion
Glutamate
Semi-dense
cytoplasmic
matrix
Gap junction
channel
ZO1
AMPA
receptor
PSD
Regulated
trafficking
PSD95
CaMKII
Removal
Figure 2 | Trafficking of channels at chemical and electrical synapses. a | Ionotropic glutamate
receptors
are trafficked
Nature Reviews
| Neuroscience
in and out of synapses. Postsynaptic densities (PSDs) provide a scaffold that helps to regulate this trafficking. PSD95 and
calcium/calmodulin-dependent protein kinase II (CaMKII) are both abundant components of PSDs. Regulated trafficking
of AMPA receptors is thought to underlie the modification of synaptic strength at glutamatergic synapses. b | There is
turnover of gap junction channels at electrical synapses. New connexons are trafficked as unpaired hemichannels to the
membrane in vesicles, where they are inserted at the periphery of the gap junction plaque and dock with hemichannels in
the apposing membrane. They are internalized as small clusters of entire channels (light grey) into either of the coupled
cells from regions near the centre of the plaque. Various proteins make up the ‘semi-dense cytoplasmic matrix’, which acts
as a scaffold for these channels. Zonula occludens protein 1 (ZO1) is a structural component of this scaffold. By contrast,
CaMKII (not shown) seems to be a non-obligatory component of the macromolecular complex, with functions that might
be similar to those at PSDs of chemical synapses.
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current flow in one versus the other direction across
the junction. Thus, such molecular asymmetry can
support rectification of electrical transmission, which,
by favouring the spread of membrane responses from
the Mauthner cell to presynaptic endings, promotes
cooperativity between auditory afferents. This association was initially observed in invertebrates 71 and
is also supported by a wealth of data on heterotypic
channels formed by recombinant connexins in cell
expression systems72–74. Although asymmetry based
on the presence of two CX36 homologues is restricted
to teleost fish (teleost fish underwent an additional
genome duplication75), the finding provided unambiguous evidence that vertebrate electrical synapses
can be asymmetrical and that such asymmetry might
underlie important functional properties. Molecular
asymmetry in electrical synapses might not be restricted
to the existence of molecularly different connexons but
could also result from post-translational modifications
of individual connexins or differences in the complement of gap junction-associated proteins forming the
semi-dense cytoplasmic matrix57, endowing electrical
transmission with more complex properties.
In summary, although chemical synapses seem
to be structurally more complex and functionally
dynamic, emerging evidence indicates that electrical
synapses might be similarly complex, diverse and
highly modifiable.
Electroretinography
An extracellularly recorded
electrical response that reflects
the activation of various cells in
the retina (including
photoreceptors, inner retinal
cells and the output ganglion
cells) in response to visual
stimulation.
Synaptic interactions during development
Gap junctional communication between neurons is
developmentally regulated: it is initially prominent but
declines at later developmental stages76,77. In the rodent
brain, this form of intercellular communication is widespread between postnatal days 5 and 12 and dramatically
decreases after postnatal day 16 to remain restricted to
some cell types76,78–81. The initial increase in coupling
enables developing neurons to form functional domains
that exhibit coordinated patterns of spontaneous activity 79,82,83. It has been proposed that the formation of these
transient domains and networks might serve as a developmental blueprint, influencing various developmental
cellular phenomena, including cell contact inhibition,
neuronal differentiation, migration, circuit formation
and the elimination of chemical synapses77.
The formation of transient gap junction networks is a
common feature of invertebrate84–87 and vertebrate76,77,80,81
nervous systems. In C. elegans, a transient network
formed by the innexin gap junction protein NSY‑5 (also
known as innexin‑19 (INX‑19)) is required for the left
and right olfactory AWC neurons to create asymmetrical patterns of gene expression during embryogenesis87.
NSY‑5 mutants failed to establish this asymmetry, suggesting that intercellular communication mediated by
NSY‑5 junctions is a critical developmental requirement 87. Similarly, transient gap junctions mediate avoidance of segmental homologous cell projections during
development in the leech88. Upon contact, the processes
of AP neurons, two identifiable homologous motor neuron-like cells, stop growing and finally retract, thus defining the topography of their neuronal arbors89–91. Recent
data suggest that transient inx1‑containing gap junctions
that are formed between the processes of homologous
AP cells mediate this developmental phenomenon88.
Neurite growth arrest did not occur in animals in which
inx1 was knocked down by the expression of a doublestrand interfering RNA (dsRNA) or in those expressing
an inx1 mutant that lacked open channel pore function
but retained the adhesive cellular binding properties
of gap junction channels88. These findings suggest that
these gap junctions act as conduits for an unknown messenger molecule that mediates avoidance of segmental
homologous cell projections.
Another well-established example of a transient
gap junction network can be found in the developing
mammalian spinal cord92–94. Developing lumbar motor
neurons communicate by gap junctions, leading to synchronous patterns of nerve activity during a period in
which muscle fibres are innervated by axons originating from multiple motor neurons92,94. The transition
from multiple innervation to the characteristic single
innervation in muscle fibres occurs at late embryonic
and early postnatal stages and is an activity-dependent
process, which results from competition between active
synapses95. It has been shown that a transient gap junction network modulates this developmental transition
from multiple- to single-fibre innervation96. Gap junctional coupling between motor neurons disappears at
late embryonic and early postnatal stages, causing a
lack of correlated activity between innervating axons
(elimination cannot occur if synapses remain synchronously activated), which in turn paves the way for synapse competition and subsequent synapse elimination
in multiply innervated muscle fibres96. Reduction of gap
junctional communication with gap junction-blocking
agents disrupted synchronous patterns of nerve activity
and enhanced synapse elimination96. Consistent with
this finding, acceleration of synapse elimination was
observed in mice lacking expression of CX40 (REF. 97), a
connexin that is expressed in developing motor neurons
and the expression of which dramatically decreases after
birth92. Together, these findings indicate that transient
gap junction networks have a primary role in gating
the transition from multiple- to single-fibre muscle
innervation.
Remarkably, the formation and subsequent elimination of gap junction coupling between neurons
was found to be correlated with the emergence of
chemical neurotransmission in several species. This
robust phenomenon was again observed in developing invertebrate 84,98,99 and vertebrate 100–102 nervous
systems. Furthermore, several studies indicate that
gap junction proteins expressed during development
are required for the formation of chemical synapses.
Flies containing mutations in the innexin genes shaking B and ogre failed to establish appropriate functional
synaptic connections in the visual system, as shown by
electroretinography103. This developmental defect could
be rescued by transgenic expression of the lost innexins
during pulpal development but not at later developmental stages103. More-direct evidence of the relationship between electrical synapses and the formation of
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chemical synapses comes from motor neurons in the
snail Helisoma trivolvis98. Manipulations that led to a
reduction of coupling between these snail motor neurons accelerated the formation of chemical synapses,
whereas exposure to cholinergic antagonists (which
block chemical neurotransmission at these synapses)
caused prolonged maintenance of electrical transmission98, suggesting an inverse relationship between the
establishment of chemical and electrical connectivity
at early stages of synaptic development.
This relationship between the formation of electrical
and chemical synapses is also observed in vertebrates.
The presence of gap junction coupling between developing spinal motor neurons also followed an inverse
relationship with the formation of chemical synapses100.
The decline in motor neuron coupling that occurs at late
embryonic and early postnatal stages is correlated with
the formation of glutamatergic synapses in these spinal
circuits100. Furthermore, exposure to NMDA receptor
antagonists arrested the developmental decline in gap
junction coupling between spinal motor neurons, suggesting that the increase in glutamatergic synaptic activity
that is generally associated with the onset of locomotion
promotes the disappearance of gap junction-mediated
networks between developing motor neurons100.
The exquisite relationship between the early presence
of electrical connections and the subsequent formation
of chemical synapses has recently been demonstrated
in the leech. The sequential development of electrical
and chemical synapses between two types of identifiable neurons that participate in a behaviourally relevant
local-bending circuit offered the possibility of directly
addressing this issue84. Synaptic transmission between
the P cell (that transduces pressure) and the motor
neuron-like AP cell is initially exclusively electrical but
becomes predominantly chemical in the adult animal.
Although electrical transmission remains in adulthood, it is considerably weakened99. Silencing inx1 in
embryonic P cells when innexin-based gap junctions are
initially forming and chemical synapses are absent (at
‘~50%’ of the way through embryonic development, a
stage defined by external morphological features after
egg deposition) prevented not only the establishment of
electrical synapses but also the development of chemical transmission99 (FIG. 3a), elegantly demonstrating the
requirement of electrical synapses for the formation of
chemical contacts.
The development of networks mediated by chemical synapses in the mouse olfactory bulb was arrested in
CX36‑knockout mice101, in which electrical transmission
is greatly reduced. This indicates that the early presence of
electrical synapses is also a prerequisite for the formation
of chemical synapses in mammals. This phenomenon was
also observed in the developing neocortex. Consecutive
divisions of individual radial glial progenitor cells normally produce sister excitatory neurons, which leads to the
formation of ontogenetic cortical columns that preferentially develop specific chemical synapses with each other
rather than with nearby non-siblings102. Sister excitatory
neurons are initially electrically coupled102, and blockade
of this communication impairs the subsequent formation
of specific chemical synapses between sister excitatory
neurons in ontogenetic cortical columns102. Finally, hippocampal long-term potentiation of glutamatergic transmission was shown to be impaired in CX36‑knockout
mice, suggesting that functional properties of chemical
synapses are also affected by the absence of electrical
synapses at early developmental stages104.
I have discussed the mechanistic relationship between
the presence of electrical synapses and the subsequent
formation of chemical connections. However, conversely,
receptors for chemical neurotransmitters and chemical
synapses have been shown to regulate the emergence and
disappearance of gap junctions during development105–107.
In vitro studies of cortical and hypothalamic neurons
indicate that, despite the fact that chemical connections
are not yet formed, activation of specific receptors for
chemical neurotransmitters regulates the expression
of CX36 at early developmental stages106. Prolonged
(2 week)106 activation of group II metabotropic glutamate receptors (mGluRs) leads to an increase in the
expression of CX36 through a cAMP–protein kinase A
(PKA)-dependent intracellular pathway, whereas activation of type A GABA receptors (GABAARs) leads to a
reduction of CX36 expression106 (FIG. 3b), indicating that
the formation of gap junctional networks relies on the
interplay between these two types of receptors. Because
GABAARs are depolarizing at these early developmental stages, their effects are mediated via calcium influx
and activation of PKC106. This developmental regulation of Cx36 expression involves regulation of both gene
transcription (mGluR-dependent increase) and protein
translation (GABAAR-dependent decrease)106. These
changes were proposed to be specific for these receptors,
and other classes of glutamate, GABA and acetylcholine
receptors are presumed not to be involved106.
Activation of glutamate receptors also reduces coupling observed at late developmental stages. As mentioned
above, blocking NMDA receptors delayed the formation
of chemical synapses in spinal motor neurons100, suggesting that the emergence of glutamatergic transmission
regulates uncoupling. This is supported by findings in the
rat hypothalamus105, in which activation of NMDA receptors at late developmental stages led to cAMP-responsive
element-binding protein (CREB)-dependent downregulation of Cx36 expression105, providing a direct mechanistic
relationship between the emergence of chemical transmission and the disappearance of neuronal gap junction
coupling (FIG. 3b).
In summary, the development of neural circuits in disparate nervous systems seems to rely critically on interactions between chemical and electrical synapses, which
reciprocally and dynamically regulate the emergence of
these two forms of transmission (FIG. 3c).
Synaptic interactions in the adult nervous system
The effects of neuromodulators on gap junction communication provide a clear example of how chemical
and electrical transmission interact in the adult nervous
system. Neuromodulators are released from presynaptic
terminals and activate specific metabotropic G proteincoupled receptors, which trigger signalling cascades
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a
b
100 ms
Uninjected
Sham
Scramble
RNAi
c
Group II
mGluR
High
6 mV
AP
Amount of CX36 GJC or
level of channel activity
P cell
Low
GABAAR
P1
NMDAR
P15
P30
Time
Electrical synapse
Chemical synapse
Gap junctions provide a
blueprint for the formation
of neuronal networks
Neurotransmitter
1
Ca2+
Synaptic
vesicle
Gap junction
channel
Ionotropic
receptor
2
Metabotropic
receptor
The formation of chemical synapses
triggers the elimination of coupling
in most neuronal cell types
Figure 3 | Electrical and chemical synapses interact during development. a | Blockade
of electrical synapse formation
Nature Reviews | Neuroscience
in leech embryos perturbs the formation of chemical synapses. Chemical synaptic potentials in an AP cell in response to a
single spike in a P cell (marked by the grey bar on the AP recordings) under control conditions (uninjected, sham-injected
and injected with scrambled double-stranded RNA) and after injection of double-stranded RNA (RNAi) that interferes
with the translation of innexin 1 in embryonic P cells, at a developmental time (~50% of the way through embryonic
development, a stage defined by external morphological features after egg deposition) at which innexin-based gap
junctions are forming but chemical synapses have not yet formed. b | Effects of signalling through type A GABA receptors
(GABAARs), metabotropic glutamate receptors (mGluRs) and NMDA receptors (NMDARs) on gap junction communication
(GJC) during development. The red line represents the increase (upward phase) and decrease (downward phase) in the
amount of neuronal GJC and expression of connexin 36 (CX36) during postnatal development. The arrows show the
direction of the change in GJC after activation of the given receptor. P1, P15 and P30 indicate postnatal days 1, 15 and 30.
c | Forms of interactions between electrical and chemical synapses during development. Gap junctions lead first (step 1) to
the formation of neural circuits. The arrival of chemical synapses (step 2) leads to the elimination of gap junctions in most
neuronal types. Part a is reproduced, with permission, from REF. 99 © (2010) Society for Neuroscience. Part b is modified,
with permission, from REF. 107 © (2013) Elsevier.
that modulate synaptic communication between target
cells (FIG. 4a). Dopamine, for example, has been shown
to modulate gap junction communication in various
vertebrate and invertebrate cell types16,19 (see REFS 16,102
for reviews), suggesting that both connexin and innexin
gap junction proteins are targets of its regulatory actions.
At electrical synapses mediated by CX36 or CX57, and
their teleost homologues, activation of dopamine can
lead to either an increase or a decrease in gap junctional conductance between neurons through a cAMPdependent mechanism that involves the activation of
PKA. That is, dopamine was observed to enhance coupling at goldfish electrical synapses108,109 and to promote
decoupling between retinal horizontal cells110–112. Two
phosphorylation sites in CX36, Ser110 and Ser293 (corresponding to Ser110 and Ser276, respectively, in its fish
homologues112,113), seem to be essential for the effects of
dopamine on electrical synapses. Recent evidence indicates that dopamine, acting via dopamine D1 and D5
receptors, can either promote PKA-mediated phosphorylation of CX36 at regulatory sites, leading to an increase
in coupling, or promote PKA-induced activation of protein phosphatase 2A and subsequent dephosphorylation
of CX36, leading to decoupling 114. This finding therefore
provides a mechanism for dopamine-induced bidirectional regulation of the strength of electrical synapses.
Dopamine can also activate D2 receptors, which leads to
a reduction in cAMP and PKA activation, and increases
coupling between rods and cones in the vertebrate retina115. Other neuromodulatory systems that regulate the
strength of electrical synapses include noradrenaline116,
serotonin117,118, histamine119 and nitric oxide120,121.
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a
Chemical synapse
b
Electrical synapse
Synaptic
varicosity
Mixed synapse
Neuromodulator
Glutamate
Synaptic
vesicle
Gap junction
channel
NMDAR
Neurotransmitter
Ionotropic
receptor
Postsynaptic
density
Metabotropic
receptor
cc
d
Heterosynaptic interaction
CaMKII
Goldfish mixed synapse
Dopaminergic
varicosity
Dopamine
NMDAR or
mGluR-mediated
signalling
mGluR
CB1R
eCB
release
D1R or D5R
PKA
Figure 4 | Types of interactions between electrical and chemical synapses in the adult
nervous
Nature
Reviewssystem. | Neuroscience
a | Neurotransmitter modulators released by nearby synaptic terminals (purple) regulate the synaptic strength of chemical
and electrical synapses through activation of G protein-coupled metabotropic receptors. Regulation at chemical synapses
could occur pre- or postsynaptically. b | Electrical and chemical synapses coexist at mixed synapses. Glutamatergic
synapses regulate the strength of electrical synapses by a postsynaptic mechanism that includes the activation of NMDA
receptors (NMDARs) and calcium/calmodulin-dependent protein kinase II (CaMKII). c | Regulation of electrical synapses
by glutamatergic transmission could also be heterosynaptic. Nearby glutamatergic synapses can regulate electrical
transmission through NMDAR or metabotropic glutamate receptor (mGluR) activation. d | Another mechanism of
interaction at goldfish mixed synapses results when synaptic activity leads to mGluR activation, which in turn triggers
endocannabinoid (eCB) release from the postsynaptic cell, and activates cannabinoid type 1 receptors (CB1Rs) on nearby
dopaminergic fibres. CB1R activation leads to dopamine release that, by activating postsynaptic dopamine D1 receptors
(D1Rs) and D5Rs and increasing protein kinase A (PKA) activity, is responsible for simultaneous enhancement of electrical
and glutamatergic synaptic transmission.
ON bipolar cells
Retinal cells that functionally
link photoreceptors (cones and
rods) to ganglion cells. ON
bipolar cells are excited by the
release of glutamate from
photoreceptors, whereas OFF
bipolar cells are instead
inhibited.
All type amacrine cells
The AII is a type of amacrine
cell (a class of retinal
interneuron) that relays
rod-driven information through
the ON‑centre cone bipolar
axons to ON‑centre ganglion
cells (output neurons of the
retina) via electrical synapses.
Regulation of electrical coupling by neuromodulators can have profound functional consequences.
Chemical and electrical synapses coexist in various circuits, raising the question of how these two networks
interact to generate function122. In the rabbit retina, rod
and cone inputs were shown to converge on cone bipolar cells19. In the case of the cones, the connection is
direct via ON bipolar cells, whereas for the rods, the connection is indirect. This indirect connection specifically
relies on electrical synapses between AII type amacrine
cells themselves and between AII type amacrine cells
and ON bipolar cells123. Both homologous and heterologous synapses are regulated by dopamine (gap
junctions between AII type amacrine cells) and nitric
oxide (AII type amacrine cells-to-ON bipolar gap
junctions), respectively, efficiently reconfiguring retinal circuits by switching between direct and indirect
pathways123,124.
Remarkably, it has been shown that fast, amino acidmediated chemical transmission also interacts with electrical synapses. ‘Mixed’ chemical and electrical synapses
found at ‘large myelinated club endings’ (or simply ‘club
endings’)52 — terminations of primary auditory afferents
on the teleost Mauthner cells — provide a unique opportunity to study interactions between these two modalities of synaptic transmission52,125 (FIG. 4b). Activation
of these synapses with high-frequency bursts (500 Hz)
of activity leads to long-lasting potentiation of both the
electrical and glutamatergic components of the mixed
synaptic potential evoked by the activation of these terminals126,127. Thus, both forms of transmission at these
contacts exhibit activity-dependent plasticity. Strikingly,
potentiation of both electrical and chemical transmission was blocked by NMDA receptor antagonists126,127,
suggesting that potentiation of electrical transmission is
initiated by the activity of the coexisting glutamatergic
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REVIEWS
synapses. The potentiations also required an increase
in postsynaptic calcium levels and the activation of
CaMKII128 (FIG. 4b). CaMKII activation was shown to
lead to an increase in gap junction conductance not only
at goldfish club endings but also in CX36‑containing gap
junctions in cell expression systems129. Consistent with
these findings, CaMKII was found to phosphorylate
CX36 at retinal electrical synapses at sites that enhance
coupling between these cells130. CaMKII is an abundant
component of the PSD at chemical synapses and has been
implicated in mechanisms of activity-dependent plasticity at chemical synapses55,131. In similarity to its interaction with the NR2B (also known as GluN2B) subunit
of the NMDA receptor at PSDs, CaMKII interacts with
CX36 by binding to its cytoplasmic domains63,131. There
are multiple CaMKIIα phosphorylation sites in CX36
and its fish homologues CX35 and CX34.7 (REFS 63,64).
Ser315 in CX36, Ser298 in CX35 and Ser300 in CX34.7
are exclusive phosphorylation sites for CaMKII (that is,
they are not targeted by other kinases)63,64. By contrast,
Ser110 and Ser293 in CX36, Ser110 and Ser276 in CX35,
and Ser110 and Ser277 in CX34.7 can be phosphorylated
by CaMKII and PKA63,64.
Mixed synapses provided unambiguous evidence that
glutamatergic and electrical synapses interact. Because
interactions occur postsynaptically (FIG. 4b), it is possible
that similar interactions could also take place hetero­
synaptically between neighbouring glutamatergic and
electrical synapses (FIG. 4c). Supporting this possibility,
ultrastructural studies have revealed that the proximity of
NR1‑containing PSDs to gap junctions in the rat inferior
olive and retina is comparable to the distances between
such PSDs and gap junctions in goldfish club endings132,133. Indeed, NMDA receptor–CaMKII-dependent
modulation of gap junction coupling has been proposed
to take place in the inferior olive132,134 and has been shown
more recently to occur in the retina130; that is, presynaptic activity of glutamatergic ON bipolar cells increases
phosphorylation of CX36 in AII type amacrine cells130.
Glutamatergic synapses have also been shown to induce
an increase in dye coupling between hypothalamic neurons135. Moreover, glutamatergic transmission has been
shown to promote activity-dependent long-term depression of electrical coupling, indicating that interactions
between glutamatergic and electrical synapses are diverse
and widespread. That is, high-frequency activation
of corticothalamic inputs triggered long-term depression of electrical transmission between thalamic relay
neurons, which required the activation of mGluRs136.
Interestingly, the interactions between chemical and
electrical synapses were club ending-specific and did not
spread to neighbouring club endings137, suggesting that
the mechanisms of PSD-initiated interactions with gap
junctions are short-ranged and take place within less than
5 μm, the usual distance between two neighbouring club
endings in the smooth Mauthner cell dendrite. Given that
plastic changes triggered by glutamate are terminal-specific and club ending afferents can be differentially activated by sounds, the gap junctions at these contacts coexist
at different degrees of conductance on the Mauthner cell
dendrite137. These findings suggest that a single cell can be
differentially coupled to its neighbours based on the activity of chemical synapses located in the proximity of each
gap junction. Inferior olivary cells, which connect to up to
40 other inferior olivary cells, have been shown to be differentially coupled with their partners. Such heterogeneity
in coupling strength has also been reported in the rabbit
retina114 and the rat cerebellar cortex 138.
In summary, by regulating nearby gap junctions,
PSDs at glutamatergic synapses provide a mechanism
for fine-tuning electrical coupling within networks of
electrically coupled neurons. This form of regulation,
by determining the probability with which neurons
interact with each other, can reconfigure networks and
create functional compartments of neurons that have a
propensity to cooperate.
Heterosynaptic interactions between electrical and
chemical synapses can be very complex and involve
intricate interactions between glutamatergic synapses
and neurotransmitter modulators. High-frequency
stimulation of club endings potentiates both electrical
and chemical transmission. This effect is dependent on
the activation of mGluR1 receptors139 and the formation
of endocannabinoids, which, by acting on cannabinoid
type 1 receptors (CB1Rs), lead to the release of dopamine from varicosities located in the close vicinity of the
club endings and Mauthner cell dendrites139. The release
of dopamine from nearby varicosities in turn leads to
the potentiation of the electrical (and glutamatergic)
synaptic response through a cAMP–PKA-mediated
postsynaptic mechanism139 (FIG. 4d). This mechanism of
potentiation illustrates the complexity and possibilities
of interactions between chemical and electrical synapses. It also demonstrates that the local availability of
dopamine is not exclusively under the control of dopaminergic neurons but that it is also determined by local
synaptic activity (both electrical and chemical).
Finally, the ‘shunting’ effect of inhibitory synapses provides another example of interactions between chemical
and electrical synapses140–142. Chemical inhibitory synaptic
conductance often short-circuits the currents that are generated at adjacent excitatory synapses by locally increasing
membrane conductance140,142. Depending on the anatomical arrangement, inhibitory conductances can dramatically reduce coupling if they are in the proximity of
electrical synapses by ‘shunting’ electrical currents before
they have had the chance to spread to a nearby neuron
through the gap junctions (FIG. 5) (see REF. 16 for a review).
This form of interaction was shown to occur within
the inferior olive glomerulus140,141 and between expansion motor neurons of the mollusc Navanax inermis142,
in which quick and transient decoupling sculpts clusters
of functionally related neurons involved in phasic behaviours. Further emphasizing the functional significance of
these fast interactions, reciprocal electrical and inhibitory
synapses organize networks of mammalian GABAergic
interneurons143. Modelling one of these interneuron networks in the cerebellum suggested that combining fast
inhibitory synapses and electrical coupling can promote
synchronized gamma oscillations143, which have been
associated with cognitive processing and are affected in
some pathological conditions144.
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a
GABAergic terminal
GABA
GABAAR
Gap junction channel
b
Reduction in
electrical
coupling
↑gCl–
Current
shunting
Figure 5 | Interactions between electrical synapses and
inhibitory chemical synapses. a | Inhibitory GABAergic
Nature Reviews | Neuroscience
synapses are often located in the vicinity of gap junctions
between dendrodendritic processes (spines) of two
neurons. b | By locally increasing membrane conductance,
inhibitory synaptic chloride conductances (gCl−) produced
by activation of type A GABA receptors (GABAARs) briefly
shunt excitatory currents to temporarily reduce effective
electrical coupling between two coupled neurons.
Associative binding
The term refers to tasks of
episodic memory that require
the associative combining of
distinct components into a
compound episode.
Are interactions involved in dysfunction?
The strong developmental inter-relationship between
electrical and chemical synapses suggests that its disruption might underlie neurological and psychiatric conditions that are acquired during development. Accordingly,
lack or dysfunction of electrical transmission could
lead, as shown in the neocortex 102 and CX36‑knockout
mice101, to subtle deficits in the formation of mature neural circuits. Interestingly, CX36 has been associated with
juvenile myoclonic epilepsy, a generalized form of epilepsy with onset in early adolescence145,146, but the exact
mechanistic linkage remains unknown. It has been suggested that some single-nucleotide polymorphisms may
influence CX36 expression and contribute to the pathogenesis of this disease by affecting the normal formation
of neural circuits145. In addition, dysfunction of glutamatergic transmission, which triggers the developmental decline in gap junctional communication via NMDA
receptor activation105, could result in abnormal levels of
electrical coupling in some brain regions that might lead
to increased neuronal synchrony and seizures147.
As previously mentioned, CX36‑mediated electrical
synapses are a feature of inhibitory interneurons in the
adult mammalian brain, including the neocortex, thalamus and hippocampus6–8,136. Inhibitory interneurons are
crucial for various brain processes, as they contribute to
the generation of gamma-frequency oscillatory activity
(30–80 Hz), which has been associated with cognitive
processing 144,148. High-frequency network oscillatory
synchronizations seem to be crucial for defining the
conscious state149 and for associative binding in learning and memory. Strikingly, these cortical gamma
oscillations are impaired in CX36‑knockout mice150,
suggesting a role for electrical synapses in generating this rhythm. Alteration of oscillatory activity has
been proposed to contribute to the pathophysiology of
schizophrenia148,151, Parkinson’s disease152 and autism
spectrum disorders153. Moreover, dysfunction of glutamatergic154–156 and dopaminergic157,158 transmission is
involved in these conditions, suggesting that dysregulation of electrical coupling could contribute to the
underlying pathophysiological processes. The investigation of these possibilities could lead to the identification of novel therapeutic opportunities for treating
these conditions.
Recent data suggest that the interactions between
chemical and electrical synapses that are observed during development have an important functional role
after brain insult. Strikingly, networks of electrically
coupled neurons identified during development can
reappear after brain injury. Adult cat spinal motor neurons become recoupled by gap junctions after peripheral nerve injury 159, re-establishing the transient gap
junction network observed during development. Gap
junction coupling was proposed to have a beneficial
functional role by helping to maintain the viability of
axotomized motor neurons until synaptic connections
with their muscle fibre targets are re-established159.
Although it is unclear if this axotomy-induced spinal
network disappears after nerve regeneration, glutamatergic transmission was shown to increase expression
of CX36 and gap junction communication in in vivo and
in vitro models of ischaemic stroke and traumatic brain
injury 107. The increase in CX36 expression occurs about
2 hours after injury and is likely to be triggered by the
massive release of glutamate from injured neurons107. As
observed during development 106, activation of group II
mGluRs has also been shown to mediate this increase
in gap junction communication160.
These interactions between glutamatergic and electrical transmission are thought to control death and
survival mechanisms in injured neurons160. A wealth
of data indicate that activation of NMDA receptors mediates the glutamate toxicity that occurs in
the injured brain161. Interestingly, electrical synapses
seem to be involved in this phenomenon. The death
of forebrain neurons evoked by intraperitoneal injection of NMDA was greatly attenuated by gap junction
blockers and in CX36‑knockout mice162,163, suggesting
that gap junctional coupling could have a deleterious
effect on neuronal survival. It has been suggested that
neurodegenerative signals could be passed to other,
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REVIEWS
a
b
Neuronal injury
Glutamate release
NMDAR
activation
Electrical
synapse
Group II mGluR
activation
Lack or dysfunction of gap
junction channels might lead
to defective formation of
neural circuits and underlie
developmentally related
neurological conditions
Chemical
synapse
Ca2+
Ca2+
overload
CX36 expression
Gap junction-permeable
‘death signals’
Penumbra
neuron
Gap junction
channel
Neuronal gap
junction coupling
Ionotropic
receptor
Enhanced
neuronal
damage
Damaged
neuron
Gap
junction
Synaptic
vesicle
Neurotransmitter
Metabotropic
receptor
Glutamate-induced
enhancement of
coupling afer injury
or stroke leads to
neuronal death
Dysregulation of
electrical synapses by
chemical synapses
might contribute to
cognitive dysfunction
Figure 6 | Interactions between chemical and electrical synapses and pathological processes. a | Chemical and
electrical synapses interact after injury. Release of glutamate from injured neurons causes neuronal damage via NMDA
Nature
Reviews
| Neuroscience
receptor (NMDAR) activation and calcium overload at the site of the lesion, and the generation
of gap
junction-permeable
‘death signals’. Simultaneous enhancement of neuronal gap junction coupling, via metabotropic glutamate receptor
(mGluR)-dependent increased expression of connexin 36 (CX36), extends neuronal damage by facilitating the passage of
these ‘death signals’ to neurons adjacent to the lesion or in the ‘penumbra’. b | A summary of potential interactions
between chemical and electrical synapses during pathological processes. The lack, or dysfunction, of gap junction
channels at early developmental stages might lead to defective formation of critical neural circuits formed by chemical
synapses, underlying developmentally related neurological conditions. During adulthood, release of glutamate from
compromised neurons after injury or stroke enhances coupling, which leads to neuronal death in uncompromised areas
adjacent to the lesion. Dysregulation of electrical synapses’ strength by neurotransmitters might contribute to cognitive
disorders. Part a is modified, with permission, from REF. 107 © (2013) Elsevier.
undamaged neurons (neurons adjacent to the lesion
or ‘penumbra’ area) as a result of the increase in neuronal coupling triggered by the activation of group II
mGluRs164 (FIG. 6a).
Conclusions
Electrical synapses have proved to be more widespread in
the mammalian brain than originally anticipated. Thus,
networks of electrically and chemically coupled neurons
are not restricted to invertebrates but seem to be a feature
of all nervous systems. This realization emphasizes the
need to further explore the functional properties of electrical synapses (of which we know significantly less than
we do about chemical synapses) and their interactions
with chemical synapses.
Studies of mixed synapses provide unambiguous evidence that, rather than unconnected lines of communication, electrical and chemical synapses cooperate and
extensively interact, and that the speed and reliability of
electrical transmission can be combined with the ability of chemical transmission to induce plastic changes.
Mixed synapses are widespread in cold-blooded vertebrates52 but they seem to be less numerous in mammals,
perhaps because of the much-improved speed of transmission observed at mammalian chemical synapses165.
However, there is growing evidence of their presence in
the mammalian nervous system, including in the spinal
cord166, in a subset of hippocampal mossy fibres167,168
and, interestingly, between dendrites of hippocampal
inhibitory interneurons169.
Interactions between electrical and chemical synapses are complex and diverse, and occur at all stages
of brain development. During development, interactions between electrical synapses are crucial for the
formation of neural circuits, whereas such interactions
in the adult brain result in dynamic reconfiguration
of hardwired networks. These interactions are likely
to have important pathological implications (FIG. 6b).
Recapitulation of some developmental interactions
between chemical and electrical synapses after brain
injury indicates that, rather than being exceptional,
these interactions constitute basic and necessary
mechanisms of communication in the nervous system.
Furthermore, the interactions between dopaminergic,
glutamatergic and electrical synapses that have been
observed in the adult brain highlight their importance
in reconfiguring neural circuits, and their dysregulation
could contribute to cognitive impairment. Future studies
are likely to confirm the intimate relationship between
the chemical and electrical modalities of synaptic transmission and shed further light on their contribution to
disease states.
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Acknowledgements
This research was supported by US National Institutes of
Health grants DC03186, DC011099, NS055726,
NS085772 and NS0552827 to A.E.P.
Competing interests statement
The author declares no competing interests.
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