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PRESYNAPTIC IONOTROPIC
RECEPTORS AND CONTROL OF
TRANSMITTER RELEASE
Holly S. Engelman and Amy B. MacDermott
Presynaptic nerve terminals are dynamic structures that release vesicular packages of
neurotransmitter, affecting the activity of postsynaptic cells. This release of transmitter occurs both
spontaneously and after the arrival of an action potential at presynaptic terminals. How is the
release process modulated? Although ionotropic receptors are commonly regarded as
postsynaptic elements that mediate the effect of the released chemical signals, a wide variety of
ionotropic receptors have also been found on presynaptic membranes near release sites, where
they powerfully influence vesicle fusion. Here, we provide an overview of the presynaptic ionotropic
receptors that modulate transmitter release, focusing on their proposed mechanisms of action.
Department of Physiology
and Cellular Biophysics and
the Center for Neurobiology
and Behavior, Columbia
University, New York, USA.
Correspondence to A.B.M.
e-mail: [email protected]
doi:10.1038/nrn1297
In the nervous system, information is transferred
between neurons at chemical synapses. Action potential
invasion of the presynaptic terminal elicits Ca2+ entry and
subsequent release of vesicular packages of transmitter
that activate postsynaptic receptors. The strength
of synaptic communication is dependent on the postsynaptic sensitivity to transmitter and on the probability
of transmitter release in response to action potential
invasion at each individual release site. Synapses with a
high probability of vesicular release influence excitability
of postsynaptic targets more reliably than synapses with a
low probability of release. Moreover, terminals with high
probability of release are more likely to undergo activitydependent depression of transmission, whereas terminals
with low probability of release readily show activitydependent facilitation of release.
Each type of nerve terminal has unique molecular
and morphological elements that contribute to its
release properties1 (FIG. 1). For example, the arrangement
of voltage-gated ion channels in the pre-terminal and
presynaptic membrane determines the shape of presynaptic action potentials, which in turn regulates the
time course and amplitude of presynaptic Ca2+ influx.
Similarly, the number and arrangement of voltage-gated
Ca2+ channels (VGCCs) with respect to presynaptic
vesicles also affects the efficacy of transmitter release.
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Multiple types of VGCC can be expressed at different
locations on the same terminal and influence transmitter release differently 2–4, and intracellular Ca2+ stores in
the presynaptic terminal can also contribute to the
dynamic changes in Ca2+ concentration that influence
transmitter release4–6.
Ionotropic transmitter receptors in the presynaptic
membrane impact on these molecular and cellular
elements, dynamically modulating release properties
and synaptic strength. Here, we will discuss the effect
that activation of different receptor types has on transmitter release. We will see that their effects on action
potential-evoked release are sometimes quite different
from their effects on spontaneous release (BOX 1).
We will contrast the impact of anionic and cationic
receptor activation, and consider when receptor permeability to Ca2+ becomes crucial for the modulation of
release. On the basis of these observations, it will
become clear that permeability of the different receptors is not predictive of their effects on transmitter
release in a simple way. Rather, cellular and molecular
elements that form part of the terminal are also crucial
in determining the nature of the modulation. Finally,
we will present evidence for the activation of receptors
by endogenous agonists and discuss the consequent
frequency dependence of synaptic transmission.
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Ca2+ store
Voltage-gated
Na+ channel
Voltage-gated
Ca2+ channel
Ih
Voltage-gated
Na+ channel
Ca2+-activated K+
channel
Voltage-gated
Ca2+ channel
Ligand-gated
ion channel
Fast-inactivating
K+ channel
Ligand-gated
ion channel
Figure 1 | Presynaptic factors that influence transmitter release. Various channels can be
N t release,
R i such
| Nas voltagei
expressed near transmitter release sites including those that enhance
gated Na+ channels and voltage-gated Ca2+ channels, and those that suppress release such as
different types of K+ channels (fast-inactivating K+ channels, Ca2+-dependent K+ channels, inward
rectifier channels (Ih )). Ca2+ stores in the terminals also contribute to the regulation of transmitter
release. Activation of ligand-gated ion channels or presynaptic ionotropic receptors can modulate
these cellular elements, thereby influencing release.
Receptor-mediated presynaptic modulation
SHUNTING
A phenomenon by which
membrane depolarization that is
induced by a given current is
attenuated because of an
enhanced membrane
conductance.
INPUT RESISTANCE
The voltage change elicited by
the injection of current into a
cell, divided by the amount of
current injected.
EVOKED POSTSYNAPTIC
CURRENTS
Synaptic currents that are
elicited by firing an action
potential in a population of
axons. They commonly reflect
release from many presynaptic
fibres, although it is possible to
study release from one or a few
fibres using so-called minimal
stimulation protocols.
136
Modulation of transmitter release at central synapses
was first hypothesized by Frank and Fuortes7, who found
that activation of flexor afferent fibres led to depression
of monosynaptic transmission onto extensor muscle
motoneurons, despite the lack of direct synaptic connections. This depression, subsequently termed presynaptic
inhibition, was later found to depend on the activation
of a Cl– conductance in the presynaptic membrane,
mediated by presynaptic GABAA (γ-aminobutyric acid,
subtype A) receptors (FIG. 2; see REF. 8 for review). Owing
to the temporal correspondence between presynaptic
inhibition and the depolarization of the primary afferent
terminals, Eccles et al.9 suggested that depolarization of
the afferents was responsible for the inhibition of transmitter release. This seemingly paradoxical inhibition of
excitation could be due to depolarization-dependent
inactivation of the voltage-gated Na+ channels that drive
the action potential10,11, or to the Cl–-mediated SHUNTING
of the Na+ currents, as found at the crayfish neuromuscular junction. Indeed, at the crayfish synapse, shunting
does not depend on depolarization, as this effect was
accompanied by membrane hyperpolarization12, and
therefore could not be due to Na+ channel inactivation.
Although these early examples of modulation of
transmitter release were shown to depend on the presynaptic action of an ionotropic receptor, subsequent
experimental attention focused on the presynaptic
actions of G-protein-coupled receptors (BOX 2).
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Only over the past ten years has new evidence been put
forward for potent regulation of transmitter release
through presynaptic ionotropic receptors. Presynaptic
ionotropic receptors that enhance as well as inhibit
transmitter release have been identified. For example,
there is clear evidence for enhanced GABA and glutamate release that depends on activation of presynaptic
nicotinic acetylcholine (nACh) receptors — cation channels that are permeable to Ca2+ and monovalent cations.
In this case, the observation that Ca2+ entry through
nACh channels enhanced spontaneous release provided
evidence for receptor localization near release sites13,14. In
other studies, activation of nACh receptors enhanced
spontaneous release, but the effect was blocked by
tetrodotoxin (TTX)15–17, a selective blocker of the
voltage-gated Na+ channels. The fact that the agonistenhanced release depended on action potential firing
indicated that the nACh receptors might have been
remote from the release sites.
In addition to receptors for ACh and GABA, other
ionotropic neurotransmitter receptors are found on
presynaptic terminals in many areas of the central
nervous system (CNS). In the following sections, we
will discuss the specific mechanisms by which these
ionotropic receptors and their cognate ligands are
thought to influence transmitter release.
Modulation through membrane potential
Ligand-gated receptors that are permeable to anions and
to monovalent cations modulate transmitter release primarily by influencing presynaptic membrane potential
and INPUT RESISTANCE. Anionic presynaptic receptors
might hyperpolarize or depolarize nerve terminals,
whereas non-selective cationic receptors depolarize the
presynaptic membrane.
Depolarization and the subsequent activation of
VGCCs can enhance spontaneous neurotransmitter
release, an effect that is sensitive to VGCC blockade. By
contrast, effects of the activation of presynaptic anionic
receptors on evoked release are more difficult to predict.
Depolarization that activates VGCCs and enhances
spontaneous release might directly enhance evoked
release. Alternatively, inhibition of evoked release could
occur, owing to blockade of action potential invasion of
the presynaptic terminal or decreasing the Ca2+ entry
that is necessary for evoked release (FIG. 3).
In some cases, the concentration of presynaptic agonists determines the sign of the effect, giving it a biphasic
nature. At low agonist concentrations, activation of a few
receptors might cause a small depolarization, enhancing
evoked release by bringing the membrane potential closer
to threshold. At higher agonist concentrations, activation
of many receptors might shunt or depress action potential amplitude to decrease release. Alternatively, complex
dependence on agonist concentration is sometimes an
indication of recruitment of several different receptor
types. A biphasic effect of presynaptic receptors might be
quite common but has been investigated in few systems.
We now turn our attention to some specific examples of presynaptic modulation that involve anionic and
cationic receptors.
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Box 1 | Evoked and spontaneous release
Evoked neurotransmitter release requires the invasion of presynaptic terminals by an
action potential. The associated membrane depolarization activates voltage-gated
Ca2+-channels (VGCCs) within the terminal, including channels that are strategically
placed near vesicle docking sites. Ca2+ entry stimulates release by promoting fusion of
synaptic vesicles with the plasma membrane. Action potentials travelling down a
single axon can synchronously evoke release of neurotransmitter from multiple
terminals on the same postsynaptic neuron, thereby producing a large response called
an EVOKED POSTSYNAPTIC CURRENT (ePSC) that can be either excitatory or inhibitory.
Many of the experiments that we review in this article have tried to distinguish
whether a given change in ePSC amplitude is due to presynaptic or postsynaptic
effects. Making this distinction has generally entailed several experimental approaches
including QUANTAL ANALYSIS, analysis of TRANSMISSION FAILURES and analysis of changes in
paired-pulse facilitation or depression. It must be emphasized that none of these
approaches are rigorously diagnostic of pre- versus postsynaptic changes.
In the absence of action potentials, transmitter release occurs in a random,
unsynchronized way by the spontaneous fusion of vesicles with the presynaptic
membrane. These release events lead to MINIATURE POSTSYNAPTIC CURRENTS (mPSCs).
The frequency of mPSCs is modulated by changes in intra- and extracellular Ca2+,
although they continue to occur in the absence of extracellular Ca2+. Because mPSCs
do not require action potential-evoked Ca2+ entry to initiate release, they are
experimentally distinguishable from evoked release by recording them in the presence
of the Na+ channel blocker tetrodotoxin. Transmitter-induced changes in the
frequency of mPSCs with no change in their amplitudes has been commonly
interpreted as an indication of the presence of presynaptic ionotropic receptors near
the release site, although postsynaptic insertion of receptors has been shown to
account for changes in mPSC frequency in at least one system89. Changes in mPSC
frequency are sensitive to relatively small changes (< 500 nM) in Ca2+ concentration at
the presynaptic terminal90. So, changes in frequency are a sensitive measure of the
presence of Ca2+-permeable ionotropic receptors, activation of VGCCs or release of
Ca2+ from intracellular stores.
Anionic presynaptic receptors. As mentioned previously, GABAA receptors were the first presynaptic
ionotropic receptors shown to inhibit evoked neurotransmitter release. Activation of GABAA and glycine
receptors, which are permeable to anions, drives
membrane potential towards the Cl– reversal potential.
Flexor afferent
Extensor afferent
Interneuron
Excitation
Excitation
Inhibition
Extensor motoneuron
Figure 2 | Presynaptic inhibition in the spinal cord. As demonstrated by Frank and
Fuortes7, flexor afferents activate inhibitory interneurons that terminate on extensor afferent
central terminals. Mediated through GABA (γ-aminobutyric acid) release from the inhibitory
interneuron, the flexor afferent inhibits transmitter release from the extensor afferent in a
process known as ‘presynaptic inhibition’.
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This potential depends on the concentrations of Cl–
in the extracellular space and in the cytoplasm.
Whereas the concentration of extracellular Cl– tends to
remain the same throughout development, cytoplasmic Cl– levels often decrease in the CNS, especially
during brain maturation18. As a result, anionic presynaptic receptors often elicit depolarization early in
development, but hyperpolarization in mature tissue.
However, there are also examples of depolarizing
responses to GABA and glycine at presynaptic sites in
the postnatal19 and adult20 nervous systems.
GABAA receptors are found on the presynaptic
terminals of dorsal root ganglia (DRG) neurons, and
their role in inhibiting presynaptic release has
been extensively studied and reviewed8. The relative
importance of changes in membrane potential versus
passive shunting as the mechanism for GABAA receptormediated inhibition of release has been investigated,
and support has been found for each of these at different
synapses10,21,22.
Interestingly, GABAA receptors have recently been
shown to enhance spontaneous release of glycine in
a manner that requires VGCC activation, while
decreasing evoked release from early postnatal rat
dorsal horn neurons23. These observations indicate
that GABAA receptor activation might depolarize the
terminals, resulting in VGCC activation and enhanced
spontaneous release, but simultaneously blocks or
shunts the presynaptic action potential, thereby
inhibiting evoked release.
Surprisingly, anionic receptors have also been shown
to enhance evoked release. Glycine receptors have an
excitatory effect on synaptic transmission at the calyx
of Held — a giant synapse at the medial nucleus of the
trapezoid body in the brainstem19. Glycine enhances
the frequency of miniature excitatory postsynaptic
currents (mEPSCs) in a manner that is sensitive to the
VGCC blocker Cd2+, consistent with depolarization
and subsequent activation of VGCCs as the underlying
mechanism. Glycine also increases the amplitude of
evoked EPSCs (eEPSCs) at this synapse, in contrast to
the effect of GABAA receptor activation on evoked
release of glycine in the dorsal horn.
The large size of the presynaptic terminal at the
calyx of Held has allowed the direct monitoring of the
effect of receptor activation on presynaptic voltage.
PERFORATED PATCH CLAMP recordings from the presynaptic
terminal, leaving intracellular Cl– concentration
intact24, revealed a depolarizing action of glycine.
Furthermore, when whole-cell recordings were made
and intraterminal Cl– levels were deliberately
decreased, the glycine-induced depolarization and
eEPSC enhancement were blocked. The ability of
glycine to enhance the eEPSC was therefore dependent
on depolarization of the presynaptic terminal.
Recently, activation of GABAA receptors has also been
shown to enhance eEPSC amplitude at the calyx of
Held25, although its effects on spontaneous release
were not explored. GABAA receptors are present early
during the development of the calyx, before glycine
receptors are present.
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a
b
c
Voltage-gated
Na+ channel
Voltage-gated
Na+ channel
Kainate
Kainate
receptor
Normalized amplitude (%)
100
Na+
Na+
Na+/
Ca2+
50
Kainate
receptor
Na+
Na+/
Ca2+
Na+/
Ca2+
0
Na+
Ca2+
Voltage-gated
Ca2+ channel
–50
Ca2+
Voltage-gated
Ca2+ channel
–100
5
20
50
200
Kainate
500
(10–9
5000
M)
Glutamate
receptors
Glutamate
receptors
Figure 3 | Concentration-dependent effect of agonist on transmitter release. a | Kainate receptors enhance or suppress transmitter release, depending on the
concentration of agonist that they are exposed to. The dose–response curve shows this effect of different concentrations of kainate on evoked excitatory postsynaptic
current (eEPSC) amplitude recorded from hippocampal CA3 neurons, normalized to control (modified from REF. 39). b, c | The schematics show how activation of
presynaptic ionotropic kainate receptors might enhance (b) or suppress (c) evoked EPSCs. Kainate receptors might be permeable to Ca2+, providing additional Ca2+ to
the terminal to enhance release. The depolarization that accompanies kainate receptor activation might enhance activation of voltage-gated Ca2+ channels at the
terminal or inhibit hyperpolarization-activated K+ channels at the terminal. On the other hand, more powerful depolarization owing to activation of more kainate
receptors might cause voltage-gated Na+ and Ca2+ channel inactivation.
Cationic, presynaptic receptors. At some synapses,
the activation of presynaptic cationic receptors such
as kainate receptors depresses evoked transmitter
release26,27. For example, excitatory transmission at
synapses between DRG and dorsal horn neurons is
Box 2 | Presynaptic modulation by G-protein-coupled receptors
G-protein-coupled receptors (GPCRs) are expressed on presynaptic terminals and can
modulate synaptic transmission. Many presynaptic GPCRs, such the GABAB
(γ-aminobutyric acid, subtype B), adenosine and cannabinoid receptors inhibit
transmitter release. These receptors act by inhibiting voltage-gated Ca2+ channels
(VGCCs) near release sites or by enhancing K+-channel activation91,92. They can also
decrease release by acting downstream of Ca2+ entry93. Other GPCRs, such as serotonin
receptors in Aplysia californica, enhance neurotransmitter release by decreasing K+
currents and prolonging the presynaptic action potential94.
Many terminals, such as sympathetic axons95, auditory giant synapses96 and
hippocampal mossy fibres42, are regulated by both GPCRs and ionotropic receptors.
The actions of GPCRs and ionotropic receptors on presynaptic terminals might differ
greatly; differences in receptor affinity, and activation and desensitization properties
between the two types of receptor will determine their net effect at a given presynaptic
terminal. So, GPCRs might act in the order of seconds or minutes, whereas ionotropic
receptors activate within a few milliseconds. These differences in activation can lead to
different temporal regulation of neurotransmitter release87. GPCRs and ionotropic
receptors can also differ in their desensitization characteristics. GPCRs desensitize
within seconds of agonist activation97, whereas ionotropic receptors desensitize over
widely variable time courses. In addition, GPCRs and ionotropic receptors that respond
to the same agonist can have markedly different affinities.
Simultaneous activation of GPCRs and ionotropic receptors can have effects that are
profoundly different from the effects of activating either type alone. For example, at
terminals where GPCRs inhibit release by suppressing Ca2+ entry through VGCCs,
activation of a Ca2+-permeable ionotropic receptor might offset this effect. Equally,
inhibitory GPCR activation might counteract the action of ionotropic receptors that
affect release by altering Ca2+ entry through VGCCs. A recent study showed a
requirement for coincident activation of presynaptic NMDA (N-methyl-D-aspartate)
receptors, ionotropic glutamate receptors and cannabinoid receptors to induce a longlasting form of synaptic depression59. This interaction between GPCRs and ionotropic
receptors increases the possibilities for signal integration at presynaptic release sites.
138
| FEBRUARY 2004 | VOLUME 5
depressed by activation of kainate receptors27. This
presynaptic action is consistent with the observation
that kainate receptors are present on dorsal roots and
near the primary afferent terminals, where they mediate
the depolarization of the primary afferent fibres28,29. As
with GABAA receptors, the simplest interpretation is
that depolarization of the primary afferent fibre drives
presynaptic inhibition of transmitter release. However,
an alternative interpretation has recently been put
forward: that this depression of evoked release is due
to a metabotropic function of kainate receptors that
results in inhibition of VGCCs (see later in text). The
relative impact of receptor-mediated depolarization
or metabotropic function at the terminals remains to
be resolved.
Kainate receptors also decrease eIPSC amplitude
at synapses between CA1 inhibitory interneurons
and pyramidal cells30–32. Interestingly, a bell-shaped,
concentration-dependent effect of kainate on the inhibition of the evoked inhibitory postsynaptic currents
(eIPSCs) was observed. This effect was postulated to be
related to the STEADY-STATE CURRENT in response to
kainate30. Activation of kainate receptors also increased
the frequency of SPONTANEOUS IPSCS (sIPSCs) in the
absence of TTX, consistent with a depolarizationinduced firing of action potentials in the inhibitory neuron as the underlying mechanism. Kainate action on
miniature IPSC (mIPSC) frequency was not uniform
among these studies. Whereas two groups30,32 have seen
a decrease in the frequency of mIPSC with kainate
application, another group has found no modulation of
mIPSCs at this synapse31.
AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid) receptor activation, both by exogenous
agonist and endogenous stimulation, decrease the
amplitude of eIPSCs between cerebellar basket cells and
Purkinje cells in 11–18-day-old rats33. High-frequency
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QUANTAL ANALYSIS
This type of analysis aims to
describe release as a function of
three basic parameters: the
number of release sites (n), the
probability of release at each site
(p), and the postsynaptic
response elicited by a single
transmitter vesicle (q). The
amplitude of a synaptic event can
be described by the product npq.
TRANSMISSION FAILURES
Cases in which a presynaptic
action potential fails to produce
a postsynaptic response.
MINIATURE POSTSYNAPTIC
CURRENTS
Currents that are observed in the
absence of presynaptic action
potentials, thought to
correspond to the response that
are elicited by a single vesicle of
transmitter. Changes in their
frequency are indicative of
presynaptic modifications,
whereas changes in their
amplitude are often interpreted
as alterations of postsynaptic
responsiveness to the
transmitter.
PERFORATED PATCH CLAMP
Variation on the patch-clamp
technique in which it is not
necessary to break the cell
membrane to gain access to the
cytoplasm of the cell to control
its voltage. Instead, the recording
pipette contains a molecule that
can perforate the membrane
(often an antibiotic), generating
pores through which cations
can flow.
STEADY-STATE CURRENT
The residual current that is
observed after a given receptor
has become desensitized or fully
activated.
SPONTANEOUS POSTSYNAPTIC
CURRENTS
Currents that are observed in the
absence of evoked action
potentials. However,
spontaneous currents are
distinct from miniature currents
in that they are sensitive to Na+
channel blockers such as
tetrodotoxin.
CLIMBING FIBRES
Cerebellar afferents that arise
from the inferior olivary
nucleus, each of which forms
multiple synapses with a single
Purkinje cell.
conditioning stimulation of excitatory CLIMBING FIBRES
decreased eIPSC amplitude and increased PAIRED-PULSE
FACILITATION at basket cell–Purkinje cell synapses. The
decrease of eIPSC amplitude was antagonized by selective AMPA receptor antagonists and was enhanced by
cyclothiazide, a drug that decreases AMPA receptor
desensitization. This effect occurred without any change
in sIPSC frequency. It is possible that presynaptic AMPA
receptors on basket cell terminals were activated by
glutamate spillover from the climbing fibres, accounting
for the depression of eIPSCs.
Recently, functional AMPA receptors have been
shown to inhibit release from central terminals of some
sensory neurons29 (FIG. 4). In a spinal cord slice preparation with the dorsal root attached, activation of AMPA
receptors reversibly decreased the amplitude of eEPSCs
elicited by dorsal root stimulation. Whereas activation
of AMPA receptors did not alter action potentials that
propagated down primary afferent axons, AMPA
applied selectively to the spinal cord in the presence of a
low Ca2+ concentration (to block secondary release of
transmitters in the dorsal horn) elicited depolarization
of primary afferents, indicating the presence of AMPA
receptors near DRG central terminals. So, similar to
kainate and GABAA receptors, the AMPA receptormediated depolarization is believed to mediate presynaptic inhibition by directly or indirectly suppressing
the action potential-mediated activation of release.
Presynaptic cationic receptors that are permeable to
Ca2+ might be expected to enhance transmitter release
owing to Ca2+ entry through the receptor itself.
However, if the receptor is not located close enough
to the terminal, the depolarizing action might predominate in causing any change in transmitter release.
For example, activation of nAChRs in the ventrobasal
thalamus elicits increases in mIPSC frequency in a Cd2+sensitive manner, indicating that the effect is not dependent on Ca2+ entry through the nAChRs but through
VGCCs. Activation of nAChRs enhances evoked release
by decreasing the failure rate of the eIPSC34. It is possible
that these receptors act by eliciting just enough depolarization to enhance, but not inhibit, the excitability of
presynaptic terminals.
Modulation that affects Ca2+ near release sites
Ca2+-permeable presynaptic receptors modify evoked
synaptic transmission by depolarization and by altering
input resistance, similar to the anionic and cationic
receptors that we discussed earlier. In addition,
Ca2+ entry through these receptors could lead to
enhancement or inhibition of evoked release by eliciting
Ca2+-dependent changes in action potential shape, or by
summating with Ca2+ entering through VGCCs or
released from intracellular stores. In the case of spontaneous transmitter release, activation of Ca2+-permeable
ionotropic receptors located on the presynaptic terminal is expected to increase release independently of
VGCC activation. Many families of cation permeable
presynaptic receptors are permeable to Ca2+. We will
consider the complex presynaptic actions that are associated with activation of these different receptor types.
NATURE REVIEWS | NEUROSCIENCE
40 pA
200 ms
SYM2081
Baseline
SYM2081
Kainate
SYM2081
Wash
Vm = +50mV
Vm = –50mV
20 ms
SYM2081 +
GYKI53655
Baseline
SYM2081 +
GYKI53655
Kainate
Figure 4 | Presynaptic inhibition and AMPA receptors.
Presynaptic AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid) receptors expressed on primary afferent neurons
depress release of glutamate onto dorsal horn neurons29. In
these experiments, the NMDA (N-methyl-D-aspartate) receptordependent evoked excitatory postsynaptic current (eEPSC)
was used to monitor glutamate release so that the impact of
blocking AMPA and kainate receptors (with GYKI53655 and
SYM2081, respectively) on eEPSC amplitude could be tested.
Presynaptic kainate receptors at the synapse between
CA3 pyramidal cells have been extensively studied. Interestingly, facilitation and LONG-TERM
POTENTIATION (LTP) at this synapse are sensitive to kainate
receptor antagonists35, as well as to philanthotoxin — a
blocker of Ca2+-permeable glutamate receptors.
Therefore, at least some kainate receptors at this synapse
are believed to be Ca2+-permeable4. It is possible that
Ca2+ entering through these kainate receptors has a role
in presynaptic modulation by recruiting intracellular
Ca2+ stores (see below). At the same time, receptor activation depolarizes the membrane potential. Activation
of kainate receptors has a concentration-dependent
biphasic effect on eEPSC amplitudes elicited in CA3
neurons by stimulation of mossy fibres36–38 (FIG. 3).
The concentration-dependent effects of kainate
receptor agonists on eEPSC amplitude might be mediated by depolarization, as they are mimicked by application of different K+ concentrations39. In fact, a biphasic
effect of somatic depolarization on action potentialevoked Ca2+ transients in mossy fibre terminals has
been reported recently40. However, the interaction
between presynaptic kainate receptor activation, mossy
fibre action potentials and transmitter release is complex and cannot be solely explained by the excitability of
presynaptic fibres.
At the synapse between mossy fibres and CA3
neurons, effects on presynaptic action potentials can be
distinguished from effects on release by examining the
properties of the PRESYNAPTIC VOLLEY. After application of
50–500 nM kainate, the mossy fibre presynaptic volley is
enhanced, possibly because the kainate-induced depolarization brings additional fibres closer to threshold41,42.
The increase in the number of activated fibres must contribute to the reported enhancement of the eEPSC by
50 nM kainate36. However, 500 nM kainate first increases
MOSSY FIBRES and
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PAIRED-PULSE FACILITATION
If two stimuli are delivered to an
axon in close succession, the
postsynaptic response to the
second stimulus is often larger
than to the first one. This
phenomenon is referred to as
paired-pulse facilitation, and is
thought to depend on the
accumulation of Ca2+ that
ensues after successive stimuli.
MOSSY FIBRES
Axons of hippocampal granule
cells, which form synapses with
CA3 pyramidal neurons. Mossy
fibre terminals are among the
largest in the central nervous
system.
LONG-TERM POTENTIATION
(LTP). An enduring increase in
the amplitude of excitatory
postsynaptic potentials as a
result of high-frequency
(tetanic) stimulation of afferent
pathways. It is measured both as
the amplitude of excitatory
postsynaptic potentials and as
the magnitude of the
postsynaptic-cell population
spike. LTP is most often studied
in the hippocampus, and is often
considered to be the cellular
basis of learning and memory in
vertebrates.
PRESYNAPTIC VOLLEY
The wave of a synaptic potential
with the shortest latency. It is
proportional to the number of
active presynaptic fibres, and its
amplitude serves to estimate the
strength of an afferent input.
UNITARY POSTSYNAPTIC
CURRENTS
Currents that result from the
activation of a single presynaptic
fibre. They often require that the
pre- and postsynaptic cells be
recorded simultaneously to
ensure that the postsynaptic
response occurs as a result of an
action potential in the
presynaptic cell.
140
and then decreases the eEPSC36,41. Likewise, although 200
nM kainate increases the fibre volley, it decreases voltagedependent Ca2+ influx and the amplitude of the eEPSC42.
Therefore, concentrations of kainate that enhance mossy
fibre action potentials can actually decrease release. This
raises the possibility that, at moderate concentrations of
kainate receptor agonist, release might be decreased by
mechanisms that are independent of changes in fibre
volley at this synapse. At high concentrations (5–10 µM),
kainate decreases the presynaptic volley, presumably
through depolarization, subsequent inactivation of Na+
channels and blockade of action potentials36,41.
Synaptically released glutamate also acts bi-directionally
through kainate receptors at mossy fibre terminals.
Glutamate release elicited by brief trains of stimulation
of either mossy fibres or CA3 collaterals leads to a facilitation of the EPSC, that is mediated by kainate receptors.
By contrast, longer stimulation trains to CA3 collaterals
decrease eEPSC amplitude36,39.
Kainate receptors also modulate inhibitory neurotransmission in a biphasic manner in the basolateral
amygdala43, where high concentrations of kainate receptor agonists depressed eIPSC amplitude and low agonist
concentrations enhanced it43. These effects were mirrored by an increase and a decrease in mIPSC frequency,
respectively, which were not prevented by blocking
VGCCs with Cd2+, possibly indicating Ca2+ entry
through kainate receptors. The authors raise the possibility that two different receptors using the GluR5 kainate
receptor subunit might be responsible for each component of the biphasic effect, analogous to the two types of
kainate receptors that are postulated to inhibit GABA
release from hippocampal interneurons44. In the
hippocampus44, depression of GABA release is mediated
by a kainate receptor with metabotropic properties, and
this effect was selectively activated by low concentrations
of glutamate without depolarization of the interneurons.
However, in the case of the amygdala, no direct evidence
for two receptor populations has been presented.
Glutamate respectively increased and decreased evoked
and spontaneous GABA release at similar concentrations. So, the underlying mechanisms of the biphasic
dose dependence of agonist action on transmitter release
seem to be different for different synapses and will have
to be established independently in each case.
Activation of the capsaicin or vanilloid receptor
TRPV1, a ligand- and heat-sensitive Ca2+-permeable ion
channel, increases spontaneous EPSC (sEPSC) and
mEPSC frequency at synapses on dorsal horn neurons45,
and routinely blocks the C-fibre-mediated eEPSC46.
Capsaicin elicits a powerful depolarization of C-fibre
cell bodies and a suppression of the C-fibre-mediated
compound action potentials28. Inhibition of eEPSC
amplitude is probably due to depolarization of the primary afferent fibres, preventing action potential invasion
of the terminal, or to a shunting of the action potential
by TRPV1 channels. In addition to deploarizing sensory
neurons, activation of TRPV1 also causes a potent elevation of intracellular Ca2+ concentration. Ca2+ must then
drive the enhancement of mEPSC frequency, despite the
depolarization-induced presynaptic inhibition.
| FEBRUARY 2004 | VOLUME 5
Activation of the NMDA (N-methyl-D-aspartate)
receptor — a Ca2+-permeable ionotropic glutamate
receptor — causes an increase in mIPSC frequency and
a decrease in eIPSC amplitude, in inhibitory cerebellar
interneurons. Such changes can be induced by direct
depolarization of the interneurons47. The NMDAinduced decrease in eIPSC amplitude might therefore
be due to depolarization of either the soma or the
presynaptic terminal. In entorhinal cortex, blocking
endogenous activation of NMDA receptors decreases
both sEPSC and mEPSC frequency, indicating that glutamate significantly enhances spontaneous release of
glutamate by acting through NMDA receptors48.
Recently, presynaptic NMDA receptors have been found
at synapses between cortical layer V pyramidal neurons.
Blockade of these NMDA receptors elicited a decrease in
mEPSC frequency and decreased amplitude of UNITARY
EPSPS evoked by high frequency stimulation of pyramidal
cells49. These data show that endogenously released
glutamate can enhance glutamate release through presynaptic NMDA receptor activation.
ATP, acting on Ca2+-permeable P2X receptors,
modulates transmitter release at many central synapses.
Activation of P2X receptors enhances glutamate release
at DRG–dorsal horn synapses in culture50 and in spinal
cord slices51,52, consistent with the ability of these receptors to depolarize the membrane potential and
with their permeability to Ca2+. Another agonist —
α,β-methylene ATP (α,β-MeATP) — stimulates both
an increase in mEPSC frequency and a decrease in
failures of transmission at the synapse between Aδ fibres
and the dorsal horn. Inhibition of ecto-ATPases —
enzymes that break down extracellular ATP — causes a
decrease in failures of transmission and an increase in
eEPSC amplitude, indicating that endogenous ATP
might modulate this synapse52.
P2X receptors have also been shown to modulate
mIPSC frequency in a subset of dorsal horn neurons in
culture53. At synapses between dorsal horn neurons,
ATP, but not α,β-MeATP, increases mIPSC frequency
and the amplitude of eIPSCs. This pharmacological
profile indicates that the relevant P2X receptors might
be different from those expressed on primary afferent
nerve terminals. A similar pharmacological profile has
been shown in acutely dissociated dorsal horn neurons
that retained their presynaptic terminals54. In this
system, ATP increases mIPSC frequency, even in the
presence of Cd2+, ruling out a requirement for depolarization-activated VGCCs. In all of these examples, Ca2+
entry through P2X receptors increases the frequency of
spontaneous transmitter release and enhances evoked
transmitter release.
Presynaptic nAChRs with variable degrees of Ca2+
permeability regulate release in various preparations
from the CNS and peripheral nervous system55. A
nAChR-mediated enhancement of glutamatergic transmission was first shown in the chick by McGehee et al.14,
studying the projection from the medial habenula to
interpeduncular neurons. Both evoked and spontaneous EPSCs were enhanced by nicotine, and these
effects were antagonized by α-bungarotoxin, pointing to
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PENTRAXIN
(or Pentaxin). Protein of discoid
appearance under the electron
microscope, consisting of five
non-covalently bound subunits.
PDZ DOMAIN
A peptide-binding domain that
is important for the organization
of membrane proteins,
particularly at cell–cell
junctions, including synapses. It
can bind to the carboxyl termini
of proteins or can form dimers
with other PDZ domains. PDZ
domains are named after the
proteins in which these sequence
motifs were originally identified
(PSD95, Discs large, zona
occludens 1).
the involvement of nAChRs that contain the α7 subunit.
Gray et al.56 also showed a nicotine-mediated enhancement of glutamate release in CA3 neurons, which
was sensitive to the α7-subunit-containing nAChRs
antagonists methyllycaconitine and α-bungarotoxin.
These authors also reported that Ca2+ concentration in
mossy fibre terminals changed in response to nicotine
application. The localization of nAChRs at mossy fibre
terminals and the existence of the Ca2+ response have
been recently challenged57, although variable detection of
Ca2+ transients after activation of nAChRs might be
owing to inconsistent triggering of Ca2+-induced Ca2+
release under different experimental conditions5.
Activation of kainate receptors enhances neurotransmission between hippocampal CA1 inhibitory
interneurons in a Cd2+-insensitive manner. Activation
with 250 nM kainate increases mIPSC frequency and
decreases failures of the eIPSC at synapses made on
interneurons58. Mulle et al.59 observed an increased
mIPSC frequency in response to 10 µM kainate at this
synapse in wild-type mice and in mice lacking the
kainate receptor subunit GluR5. However, they found
no modulation in mice lacking GluR6, another kainate
receptor subunit. Therefore, the increase in mIPSC frequency at the synapse between interneurons is probably
due to activation of Ca2+-permeable, GluR6-containing
kainate receptors.
AMPA receptors enhance spontaneous inhibitory
transmitter release. In stellate cells of the developing
(11–13-days-old) mouse cerebellum, AMPA receptor
agonists elicit increases in both sIPSC and mIPSC
frequency60. These effects are only partially blocked
by Cd2+, implicating the presynaptic involvement of Ca2+permeable AMPA receptors. In the adult cerebellum, this
presynaptic modulation is no longer present, pointing to
the developmental loss of this presynaptic receptor.
We have also obtained evidence for AMPA receptormediated increases in mIPSC frequency in the dorsal
horn (H.E., R. L. Anderson and A.B.M, unpublished
data). AMPA application increases mIPSC frequency,
but not amplitude, in a subpopulation of dorsal horn
neurons. This increase shows varying sensitivity to Cd2+,
indicating that Ca2+-permeable AMPA receptors might
allow Ca2+ entry into the terminal, which in turn
supports the release of GABA/glycine. In contrast to the
cerebellum, this modulation persists in the dorsal horn
of the young adult.
Activation of nAChRs enhances mIPSC frequency in
the dorsolateral geniculate nucleus of the thalamus34.
Nicotinic agonists increase mIPSC frequency in this
nucleus in a Cd2+-resistant manner. Nicotine can also
evoke an increase in the frequency of glycine-mediated
mIPSCs in the dorsal horn of the spinal cord61. This
effect is also Cd2+-resistant, indicating that Ca2+ entry
directly through the receptor is involved in the effect.
As discussed previously, however, other examples of
nAChR activation do not seem to indicate a role for
Ca2+ entry through the receptor, possibly owing to its
location. Nicotine elicits a concentration-dependent
increase in sIPSC frequency, but has a biphasic effect
on eIPSC amplitude in the lateral spiriform nucleus
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of chick brain62. Low concentrations of nicotine
(50–100 nM) enhance eIPSC amplitude, whereas higher
concentrations (0.5–1 µM) decrease it. Because mIPSCs
were not assessed in this study62, the site on which
nicotine is acting in this system in not known.
Ca2+ release from intracellular stores. Recently, two
groups have reported presynaptic modulation of glutamate release onto CA3 hippocampal neurons by Ca2+permeable ionotropic receptors; modulation that
involves Ca2+-induced Ca2+ release from intracellular
stores4,5. Activation of nAChRs elicits an increase in
frequency and amplitude of mEPSCs recorded from
CA3 pyramidal neurons. These increases are sensitive to
extracellular Ca2+ and are blocked by drugs that empty or
prevent refilling of intracellular Ca2+ stores5. These results
indicate that Ca2+ entering through nAChRs elicits Ca2+
release from intracellular stores, which then facilitates
vesicle fusion. Recruitment of Ca2+ stores results in the
potent effect of nicotinic agonists in this preparation.
Kainate receptors also modulate transmission at
the mossy fibre–CA3 synapse. As mentioned previously,
mossy fibre LTP is antagonized by kainate receptor
antagonists35, and these receptors are thought to be Ca2+
permeable. It has been shown that LTP at this synapse is
reduced by emptying Ca2+ stores, and that the effect of
the antagonists is also reduced by this manipulation4.
So, Ca2+ entry through kainate receptors is thought to
trigger Ca2+-induced Ca2+ release from intracellular
stores, contributing to mossy fibre LTP4. The role of
Ca2+ stores in the actions of presynaptic ionotropic
receptors at other synapses remains to be investigated.
Modulation independent of ion flow
Ionotropic receptors are known to associate with many
other proteins through their cytoplasmic and extracellular domains. AMPA receptors, for example, can be
clustered extracellularly by a protein known as neuronal
activity-regulated PENTRAXIN (NARP)66. The cytoplasmic
tails of the different AMPA receptor subunits can
bind PDZ DOMAIN-containing proteins, such as synapseassociated protein 97 (SAP97)67, glutamate-receptorinteracting protein (GRIP)68, AMPA receptor-binding
protein (ABP)69, protein that interacts with C kinase 1
(PICK1)70 and stargazin71, all of which might form part
of larger signalling complexes. In addition, the cytoplasmic domain of the AMPA receptor subunit GluR2
associates with the N-ethylmaleimide-sensitive fusion
protein (NSF)72,73. AMPA receptors can also associate
with the tyrosine kinase lyn74 and with G-protein subunits75. So, through their association with these proteins,
AMPA receptors might trigger changes that are independent of ion flux, which might in turn promote changes in
the readily releasable vesicle pool or in vesicle fusion.
There are several examples of ionotropic receptors
that modulate transmitter release for which the underlying mechanism seems to be independent of the
permeating ions. Rodríguez-Moreno et al.44,76 have
proposed a metabotropic-like function for kainate
receptors that are present near hippocampal GABA
release sites on CA1 interneurons. In this case, the
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Table 1 | Modulation of spontaneous and evoked release mediated by presynaptic ionotropic receptors
Neurotransmitter
Ionotropic
receptors
Effect on
spontaneous release
Effect on evoked
release
Glutamate
NMDAR
Increase
Decrease
Cerebellum
IPSC
47
Kainate R
Increase
Biphasic
Dorsal horn
IPSC
26
Kainate R
Decrease
Decrease
Hippocampus,
onto CA1
IPSC
30,32
Kainate R
No change
Decrease
Hippocampus,
onto CA1
IPSC
31
Kainate R
Increase
Increase
(decrease failures)
Hippocampus,
between inhibitory
neurons in CA1
IPSC
57
Kainate R
Biphasic
Biphasic
Amygdala
IPSC
43
nAChR —
Ca2+-perm.
Increase
Increase
Medial habenula
EPSC
14
nAChR —
Ca2+-perm.
Increase
Increase
Ventrobasal
thalamus
IPSC
34
nAChR —
Ca2+-imperm.
Increase
Increase
Dorsolateral
geniculate thalamus
IPSC
34
P2X
Increase
Increase
Dorsal horn
IPSC
52
P2X
Increase
Increase
(decrease failure)
Dorsal horn
EPSC
51
ACh
ATP
Brain area
IPSC or EPSC
References
GABA
GABAA
Increase
Decrease
Dorsal horn
IPSC
23
Glycine
Glycine
Increase
Increase
Trapezoid body,
auditory brainstem
EPSC
19
?
VR1
Increase
Decrease
Dorsal horn
EPSC
45,46
ACh, acetylcholine ; EPSC, excitatory postsynptic current; GABA, γ-aminobutyric acid; imperm., impermeable; IPSC, inhibitory postsynaptic current ;
NMDAR, N-methyl-D-aspartate; R, receptor; P2X, purinergic receptor 2X; perm., permeable.
PERTUSSIS TOXIN
The causative agent of whooping
cough, pertussis toxin causes the
persistent activation of Gi
proteins by catalysing the ADPribosylation of the α-subunit.
PARALLEL FIBRES
The axons of cerebellar granule
cells. Parallel fibres emerge from
the molecular layer of the
cerebellar cortex towards the
periphery, where they extend
branches perpendicular to the
main axis of Purkinje neurons
and form so-called en passant
synapses with this cell type.
LONG-TERM DEPRESSION
(LTD). An enduring weakening
of synaptic strength that is
thought to interact with long
term potentiation (LTP) as
cellular mechanisms of learning
and memory in structures such
as the hippocampus and
cerebellum.
142
G-protein inhibitor PERTUSSIS TOXIN and selective blockers
of protein kinase C prevented the inhibition of eIPSCs
by kainate, without influencing the ability of kainate to
drive action potential firing in the inhibitory neurons44.
Rozas et al.77 have subsequently shown that activation of
kainate receptors in DRG neurons causes inhibition
of VGCCs, and that this effect is sensitive to pertussis
toxin77. This pathway provides a possible mechanism
for the inhibitory action of kainate both at synapses of
sensory afferents in the dorsal horn and in hippocampal
interneurons.
Presynaptic NMDA receptors at the PARALLEL
FIBRE–Purkinje cell synapse in the cerebellum constitute
another case in which the modulation of release does
not depend directly on ion flux through the receptor78.
Instead, activation of NMDA receptors induces the
synthesis of nitric oxide, which functions as a modulator at this synapse. Application of NMDA decreases the
eEPSC, but it does not change the presynaptic volley,
nor does it alter paired-pulse facilitation, indicating
that NMDA does not act by directly affecting the
presynaptic action potential or altering release.
However, presynaptic NMDA receptors are believed to
be responsible for this effect for two reasons. First,
NMDA receptors are not believed to be present on
Purkinje cells (the postsynaptic neuron in this case) in
mature animals. Second, the application of NMDA
receptor agonists must be paired with parallel fibre
stimulation to elicit eEPSC depression. This NMDAinduced depression is sensitive to inhibitors of nitric
oxide (NO) synthase and of guanylate cyclase.
| FEBRUARY 2004 | VOLUME 5
The authors hypothesize that NMDA triggers NO
production, and that NO travels to the postsynaptic
site to stimulate guanylate cyclase and decrease the
response of the Purkinje cell. It is worthwhile noting
that when postsynaptic Ca2+ buffering is reduced,
NMDA elicits a longer depression, which occludes the
induction of LONG-TERM DEPRESSION (LTD) at this synapse.
These presynaptic NMDA receptors might be involved
in this form of cerebellar LTD, an idea that is further
supported by the sensitivity of LTD to the NMDA receptor antagonist 2-amino-phosphonovalerate (APV)79.
TABLE 1 provides a summary of the action of the
different receptors that we have discussed, trying to
distinguish between effects on spontaneous and evoked
release.
Source of endogenous agonist
The sources of endogenous agonists that activate
ionotropic presynaptic receptors have generally been
difficult to identify, with the exception of synapses
between reciprocally connected cells or in the case of
autoreceptors. As most ionotropic receptors have relatively low affinity, the source of the transmitter should
be close by to ensure a transmitter concentration that is
sufficiently high for receptor activation. This implies
that the most effective means for activating presynaptic
ionotropic receptors is through release from closely
apposed terminals, although spillover from nearby
release sites might also be effective. This release could be
glial80, dendritic (BOX 3), axonal or from the presynaptic
terminal itself in the case of autoreceptors.
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Box 3 | Dendritic release
Dendritic release might turn out to be an important feedback mechanism in the nervous
system, and to be powerfully regulated by ionotropic receptors.
Dendritic sites of vesicular release have been morphologically identified in several
locations, including the spinal cord98–100, olfactory bulb101 and thalamus102,103. Dendritic
release is initiated by action potentials backpropagating into dendrites (as in the case of
granule cell dendrites in the olfactory bulb104), by action potentials originating in
dendrites, or by activation of synaptic ion channels105.
The best-studied system in which dendritic release is regulated by ionotropic receptors is
in the olfactory bulb. NMDA (N-methyl-D-aspartate) receptors on granule cell dendrites
have powerful effects on neurotransmitter release.Whereas axonal presynaptic receptors
modulate release, these dendritic receptors elicit phasic transmitter release. Reciprocal
dendrodendritic release from granule cells has been shown to be dependent on NMDA
receptor activation106, and can be initiated independently of voltage-gated Ca2+ channels
by glutamate release from mitral cell dendrites paired with action potentials in the granule
cell, resulting in Ca2+ currents through granule cell NMDA receptors107.
GABAA (γ-aminobutyric acid, subtype A) receptors also influence dendritic release. For
example, synaptic activation of GABAA receptors at dendrodendritic synapses along
mitral cell secondary dendrites has been shown to block distal propagation of action
potentials in the mitral cell soma108. This would be expected to decrease glutamate release
from distal dendrites of mitral cells.
As in axons, dendritic release is regulated by the interplay between ionotropic receptors
and voltage-gated channels. Dendrites express various K+ channels similar to axons, with
expression patterns and densities that depend on the neuron type109. Some dendritic K+
channels have been studied for their impact on dendritic release. For example, in the
olfactory bulb, KA channels in granule cell dendrites limit the synaptic depolarization that
is elicited by AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)
receptors110, whereas the longer-lasting, NMDA-induced depolarization outlasts the KA
current and can subsequently influence dendritic transmitter release.
Presynaptic kainate receptors provide the best examples of the impact of endogenously released agonist on
presynaptic hetero- and autoreceptors (FIG. 5). The
synapse between inhibitory interneurons and pyramidal
neurons in area CA1 of the hippocampus is subject
to presynaptic inhibition by endogenously released
glutamate from brief, high-frequency stimulation of
81
SCHAFFER COLLATERALS . Glutamate that is released by these
SCHAFFER COLLATERALS
Axons of the CA3 pyramidal
cells of the hippocampus that
form synapses with the apical
dendrites of CA1 neurons.
a Parallel fibre to stellate cells
10 Hz
20 Hz
33 Hz
100 Hz
50 pA
b Parallel fibre to Purkinje cells
Control
NBQX
50 pA
200 ms
Figure 5 | Target-dependent effects of autoreceptors. Activity-dependent activation of
presynaptic kainate autoreceptors causes different effects at different synapses (taken from fig. 7
in REF. 88). NMDA (N-methyl-D-aspartate) excitatory postsynaptic currents are recorded in the
presence of an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor
antagonist from parallel fibre to stellate cells (a) and parallel fibre to Purkinje cells (b) in cerebellar
slices in the absence (dark green lines) and presence (green lines) of tetrodotoxin. Endogenously
activated presynaptic kainate autoreceptors depress the parallel fibre to stellate cell synapse
when activated at high frequency, whereas they enhance the parallel fibre to Purkinje cell synapse
when activated at high frequency. NBQX, 6-Nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione.
NATURE REVIEWS | NEUROSCIENCE
axons is effective in reducing eIPSC amplitude even
100 msec after the last conditioning stimulus is applied.
Interestingly, paired recordings of presynaptic interneurons and postsynaptic CA1 pyramidal neurons have
shown that glutamate released from Schaffer collaterals
enhances unitary IPSCs acting through kainate receptors in interneurons82. Similarly, the activity-dependent
release of glutamate from the postsynaptic neuron
itself 83 has been shown to inhibit GABA release acting
through presynaptic kainate receptors in the cortex.
Presynaptic kainate autoreceptors have been found
in several systems. For example, they mediate the
frequency-dependent facilitation and depression of
glutamate release from mossy fibres4,35,36,39,84,85. Indeed,
a single action potential is sufficient to activate presynaptic kainate autoreceptors, resulting in afterdepolarization, which causes enhanced Ca2+ entry
during a subsequent action potential and increased
evoked release86. In developing thalamocortical synapses,
frequency-dependent depression of eEPSCs was shown
to be partly due to released glutamate acting on presynaptic kainate autoreceptors87. Glutamate from parallel
fibres in the cerebellum can increase or decrease its own
release from these terminals by activation of kainate
receptors. The nature of this modulation depends on
the frequency of stimulation and on whether the postsynaptic neuron is a Purkinje cell or a stellate cell88.
Activation of presynaptic NMDA receptors by
endogenous glutamate has been shown in entorhinal
and visual cortices, where blockade of these receptors
decreases mEPSC frequency48,49, as mentioned previously. In the visual cortex, NMDA receptor antagonists
modulate the eEPSP between pyramidal cells in response
to high-frequency (30 Hz), but not low-frequency
(0.1 Hz) stimulation, indicating that glutamate might act
on NMDA autoreceptors49.
Functional relevance of presynaptic modulation
Presynaptic ionotropic receptors are found throughout
the brain, and their impact on neuronal activity is
becoming increasingly apparent. These receptors
dynamically control transmitter release at both axonal
and dendritic release sites. As we have seen, action
potential-evoked release can be enhanced, depressed or
completely blocked, depending on the receptor itself
and on the timing of endogenous agonist presentation.
Moreover, the impact of presynaptic receptor activation
can last for minutes or hours, as in the case of nAChRs
that recover slowly from desensitization63, or for a few
seconds, as in the case of presynaptic kainate receptors
on mossy fibre terminals36,39. Endogenous activation can
be so rapid as to account for the short-term facilitation
that has been recorded during studies of paired-pulse
facilitation87. Indeed, kainate receptors at the developing
thalamocortical synapse depress neurotransmission only
at high frequencies (50–200 Hz)87. This involvement of
presynaptic ionotropic receptors in short-term facilitation or depression of release might be more widespread
than previously expected. Indeed, their rapid activation
kinetics make them suitable to mediate such shortterm effects.
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Increasing the potential complexity of the action of
presynaptic ionotropic receptors is the observation that
they might not regulate spontaneous release in the same
way as evoked release (TABLE 1). For example, presynaptic
GABAA receptor activation can increase inhibitory tone
by increasing spontaneous, quantal release of glycine onto
dorsal horn neurons, and at the same time depressing
evoked release. Moreover, the effects of presynaptic
ionotropic receptors can be biphasic, as shown for kainate
receptors at several synapses in the CNS. In addition, the
control of release is determined by the homosynaptic,
heterosynaptic and even glial release of agonists.
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Presynaptic ionotropic receptors provide an
important form of cross-talk between elements of
neuronal circuits. They are also putative targets
of drug action. In the case of nicotine, for example,
presynaptic ionotropic receptors have been shown to
account for most of its principal actions on central
neurons. It can be predicted that this field will
continue to develop as new insights into synaptic
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physiological processes.
Recording from large presynaptic terminals, these
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Acknowledgements
Our work has been supported by the Christopher Reeves Paralysis
Foundation and the National Institutes of Health.
Competing interests statement
The authors declare that they have no competing financial interests.
Online links
DATABASES
The following terms in this article are linked online to:
LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/
AMPA receptors | GABA receptors | Glycine receptors |
Kainate receptors | nACh receptors | TRPV1 | NMDA receptors |
P2X receptors
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