Epilepsy: A Comprehensive Textbook
2nd Edition
© 2008 Lippincott Williams & Wilkins
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Chapter 22
Excitatory Synaptic Transmission
Karen S. Wilcox
Peter J. West
Marc A. Dichter
Introduction
Information processing throughout the central nervous system (CNS) occurs through synaptic transmission between neurons coupled via chemical synapses. Excitability at chemical synapses is controlled by both the amount of excitatory neurotransmitter released and by the way in which the postsynaptic neuron responds to the released transmitter. Multiple regulatory mechanisms exist within the CNS to maintain a controlled and focused level of excitability and to prevent excess excitation. These include mechanisms intrinsic to excitatory systems and mechanisms extrinsic to these systems; regarding the latter, direct inhibition and indirect modulation are noteworthy. Excess activation of excitatory pathways in specific circuits can lead to epileptic activity, neuronal damage, and even cell death. This chapter discusses what is known concerning the inotropic and metabotropic glutamate receptors that underlie excitatory synaptic transmission and the role(s) that they play in epilepsy.
Excitatory Neurotransmitters
A variety of endogenous compounds have been identified as agonists at excitatory amino acid (EAA) receptors. However, the two EAAs that are thought to be the most likely neurotransmitter candidates are L-glutamate and L-aspartate. Both compounds act as agonists at all subtypes of inotropic glutamate receptors. Other endogenous compounds present in the CNS that act as agonists at EAA receptors and can depolarize neurons include N-acetylaspartylglutamate (NAAG), quinolinic acid, and the sulfur-containing amino acid analogs of glutamate: Cysteic acid, homocysteic acid, cysteine sulfinic acid, homocysteine sulfinic acid, and S-sulfocystein.28 Whether any or all of these act as neurotransmitters at specific synaptic sites remains to be determined.
Glutamate Synthesis and Uptake Mechanisms
Glutamine and α-ketoglutarate are thought to be the major precursors for glutamate, which is subsequently packaged into vesicles for future release into the synaptic cleft. Glutamine is taken up into the presynaptic terminal via an active, sodium (Na)-dependent uptake protein. It is then transported to mitochondria, where it is converted via phosphate-activated glutaminase to glutamate and ammonia. α-Ketoglutarate is also actively taken up into the presynaptic terminal, where it is transaminated into glutamate. The glutamate anion in the terminal is then actively taken up into vesicles for future release. Upon release into the cleft, the glutamate either is actively taken back up via a neuronal glutamate transporter and repackaged, or it diffuses away from the cleft and glial glutamate transporters, most often excitatory amino acid transporter (EAAT)-2, internalize the extracellular glutamate.17
Once in astrocytes, the glutamate can either be (a) released again into the synaptic cleft via a calcium-dependent vesicular release,13 (b) metabolized via glutamine synthetase into glutamine, or (c) metabolized into α-ketoglutarate by either glutamate oxaloacetate transaminase or glutamate dehydrogenase. This glutamine and α-ketoglutarate is then actively transported out of the glial cells and back into the presynaptic terminals for subsequent resynthesis of glutamate (Fig. 1).51 Recent work by a number of groups suggests that patients with temporal lobe epilepsy (TLE) may have a deficiency in glutamine synthetase in the astrocytes of sclerotic tissue. This reduced glutamine synthetase may underlie the elevation in extracellular glutamate often associated with TLE47,155 by reducing the rate of glutamine–glutamate cycling.119
Clearly, glutamate uptake molecules perform a vital function in maintaining large precursor levels for glutamate synthesis and low extracellular concentrations of glutamate. To date, five high-affinity glutamate transporter proteins have been cloned.17,66,67,120,145 All five transporter proteins have been shown to be sodium-dependent, and they are preferentially located in neurons, astrocytes, or other types of glial cells. The recent development of highly specific antagonists of these glutamate transporters will prove quite valuable in ascertaining the contribution these transporters make to neurotransmission at excitatory synapses.
Ionotropic Excitatory Amino Acid Receptors
Three pharmacologically distinct classes of inotropic glutamate receptors (iGluRs) have been identified. The names of these iGluR subfamilies are based on the synthetic agonists that bind to the specific receptor subtypes and selectively open the associated ion channels: The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, the kainic acid (KA) receptor, and the N-methyl-D-aspartate (NMDA) receptor. This initial pharmacologic classification was supported by the subsequent identification of separate gene families whose sequence similarities were correlated with their affinity for the agonists previously described: GluR1 through GluR4 (which encode AMPA receptor subunits); GluR5 through GluR7; KA1 and KA2 (which encode low- and high-affinity KA receptor subunits, respectively); and NR1, NR2A through NR2D, and NR3A and NR3B (which encode NMDA receptor subunits). Two orphan receptor subunits, GluRδ1 and GluRδ2, have also been identified.69
FIGURE 1. Schematic diagram of a model excitatory synapse.
All iGluR subunits have an extracellular N-terminus, an intracellular C-terminus, three transmembrane domains (M1, M3, M4), and a membrane re-entrant loop (M2) that forms the pore (Fig. 2). The ligand binding domain of iGluRs is formed by
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stretches of amino acids in the N-terminal domain (S1) as well as the linker between M3 and M4 (S2). This ligand binding domain has been crystallized in various functional conformations, and has provided insight into key features of glutamate receptor agonist affinities, activation, desensitization, subunit association, and receptor assembly. Several articles offer excellent in-depth review of this topic.86,92,93 Functional receptor-gated ion channels are formed when subunits within, but not between, families come together to form homo- or hetero-oligomers. Although the precise subunit stoichiometry of iGluRs was debated for some time, recent studies now suggest that these receptors are composed of four subunits.91 The reader is directed to several excellent reviews on this topic.42,69,139
AMPA Receptors
Molecular Biology
Post-transcriptional Modification.
The AMPA receptor subunits GluR1 through GluR4 are each comprised of approximately 900 amino acids and share approximately 70% sequence homology. Additional diversity among the subunits can be generated by post-transcriptional modifications (alternative splicing and RNA editing). All four AMPA receptors undergo alternative splicing of a 38-amino acid sequence in the extracellular domain between M3 and M4. This gives rise to two splice variants, “flip” and “flop.”141 These receptors exhibit differing biophysical and pharmacologic characteristics; the flip variant tends to desensitize more slowly and to a lesser extent than do flop variants, which can influence the amplitude of the AMPA receptor responses.104 Flip variants also have a greater sensitivity to the allosteric modulator cyclothiazide than do the flop variants. Expression levels of these variants are regulated developmentally, regionally, and in a cell-type–specific manner, and are also modified by disease states such as epilepsy.
In addition to the flip and flop splice variants, the GluR1, GluR2, and GluR4 AMPA receptors can undergo alternative splicing of their C-termini. This splicing results in isoforms with “long” and “short” cytoplasmic C-terminal domains, and these variants are named as such. Variation in the length of these receptors’ C-terminal domains can influence their interactions with cytoplasmic proteins through the presence (“short” C-termini) or absence (“long” C-termini) of a PSD-95/Disc-large/ZO-1 (PDZ) binding domain.39
FIGURE 2. Schematic diagram of iGluR structure within membrane.
It has been observed that homomeric or heteromeric AMPA receptors that lack the GluR2 subunit are permeable to calcium and exhibit a voltage-dependent block by intracellular polyamines that results in an inwardly rectifying current-voltage (IV) relationship. The ability of the GluR2 subunit to influence these AMPA receptor properties resides in a single amino acid substitution (the genomically encoded glutamine is converted to arginine) in the pore forming M2 segment. This Q/R substitution is the consequence of post-transcriptional editing of premessenger RNA.142 AMPA receptors that contain edited GluR2(R) are impermeable to
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calcium, have a low single-channel conductance, and have linear IV relationships.147 Most neurons in the adult CNS have been shown to possess AMPA receptors with these qualities, and this suggests that the GluR2(R) subunit is a constituent of most native AMPA receptors. One notable exception to this rule is receptors expressed in various interneurons that appear to be calcium permeable, inward-rectifying, and are therefore believed to lack the GluR2 subunit.73
A second known post-transcriptional modification to AMPA receptors via RNA editing is the substitution of the genomically encoded arginine (R) for glycine (G) in GluR2, GluR3, and GluR4. This R/G site is located just before the flip/flop cassette in the extracellular domain between M3 and M4. Generally speaking, homomeric and heteromeric assemblies of edited (G) receptors have faster kinetics for recovery from desensitization (resensitization) than do their unedited (R) counterparts. Variations also occur in the kinetics of desensitization in edited (G) versus unedited (R) receptors, with a tendency toward slower desensitization rates. Akin to the other post-transcriptional splice variants and RNA-edited forms of AMPA receptors, the R/G edit progresses with brain development in a subunit and splice variant-dependent manner.42
Post-translational Modifications.
As another way to generate additional diversity, AMPA receptors also undergo post-translational modifications in the forms of glycosylation and phosphorylation. All AMPA receptors contain extracellular glycosylation sites but different subunit combinations appear to be affected differently by the presence or absence of bound oligosaccharides. For example, with the exception of GluR2, the lectin concanavalin-A potentiates AMPA receptor–mediated currents by binding to these carbohydrates and inhibiting desensitization.50 Although it is not entirely clear what the function of glycosylation is in these receptors, it is thought that this modification is involved in the maturation and transport of receptors and possibly the protection of AMPA receptors from degradation.116
Additionally, AMPA receptors have been shown to be phosphorylated basally or in response to varying types of synaptic activity. Although commonalities exist, the particular phosphorylated amino acid residues and kinases responsible for these modifications vary on a subunit basis. Phosphorylation of these residues leads to alterations in the receptor-gated channel properties. One of the most extensively studied instances of this phenomena is the phosphorylation of specific residues in the C-terminal domain of GluR1. GluR1 subunit phosphorylation potentiates receptor activation and leads to an increase in channel conductance and open probability,7,38,124 and these modifications have been shown to be involved in forms of plasticity such as long-term potentiation (LTP) and long-term depression (LTD).76 A complete description of this work is beyond the scope of this review, and the reader is directed to an excellent review.116
Structure and Function of AMPA Receptors.
The structure of the ligand-binding core of AMPA receptors, as well as other iGluRs, has been determined through the application of X-ray diffraction, and this has led to considerable insight into the molecular mechanisms of receptor activation and desensitization.56 By using a water-soluble construct of the li- gand binding domain (S1 and S2), the structure was determined to have a hinged clamshell shape, in which the agonist binds in the cleft between each shell. In the absence of agonist, the clamshell is mostly open, whereas in the presence of agonist, the clamshell closes to varying degrees depending on the particular agonist. The degree of closure was shown to correlate with the degree of receptor activation (in which kainate, a partial agonist for AMPA receptors, caused an intermediate degree of closure relative to the full agonists AMPA and glutamate). Furthermore, competitive antagonists like 6,7-dinitro-quinoxaline-2,3(1H,4H)-dione (DNQX) were shown to stabilize the open conformation of the ligand-binding clamshell. Finally, the observation that these receptor fragments tended to favor crystallizing as dimers led to hypotheses and subsequent studies examining the tetrameric stoichiometry of these receptors (a dimer of dimers), as well as the conformational changes that are necessary for the closing of the clamshell
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binding pocket to translate to opening of the channel and desensitization of the receptor complex.
Electrophysiology
As noted earlier, the ligand-binding pocket of iGluRs consists of a bilobed “hinged clamshell” structure that adopts differing conformations in the absence or presence of agonist. Upon binding of the full agonists glutamate or AMPA, the cleft between the two lobes (S1 and S2) closes by approximately 20 degrees relative to each other, whereas binding of the partial agonist kainate induces a cleft closure of approximately 12 degrees.56,86 In either event, this cleft closure is coupled to receptor activation and ion channel opening. In most natively expressed receptors, the ion channel is equally permeable to Na+ and potassium (K+), and the resulting current has a depolarizing effect on the neuron by driving the membrane potential toward an equilibrium potential of approximately 0 mV. However, in AMPA receptors that either lack the GluR2 subunit, or in which the GluR2 subunit is unedited, there is also a significant permeability to calcium (Ca2+).
Electrophysiologic studies using single-channel recordings of recombinant AMPA receptors have shown that homo- and heteromeric channel assemblies display multiple conductance levels whose amplitudes vary in a subunit-dependent manner, as well as in response to post-transcriptional and post-translational modifications.38,129,147 For example, homomeric receptors composed of the unedited GluR4(Q), as well as heteromeric receptors composed of unedited GluR4(Q) and GluR2(Q), have single-channel conductance between 20 and 30 picosiemens (pS). On the other hand, inclusion of edited GluR2(R) into these heteromeric assemblies reduces the conductance to approximately 10 pS, and homomeric assemblies of GluR2(R) have conductances in the femtosiemens (fS) range.147 Native AMPA receptors in a variety of neurons have single-channel conductance similar to those reported for recombinant receptors. For example, cultured cerebellar granule cells have AMPA receptors that fall into three categories based on their single-channel conductance: High–conductance (10–30 pS), low-conductance (5–10 pS), and femtosiemens channels (<1 pS).35,162
One of the most dramatic features of this receptor, relative to the NMDA receptor, is the rapid desensitization observed when the receptor is exposed to the full agonists AMPA or glutamate.151,154 After rapid application of an agonist, the channel opens. However, in the continued presence of the agonist, the amount of current flow is rapidly reduced, with a time constant of decay of <10 msec. If the agonist application is terminated and then reapplied, the current is again quite large, so that desensitization does not last long in the absence of agonist. Electrophysiologic studies have led to the conclusion that desensitization probably contributes, at least in part, to the rapid decay of excitatory postsynaptic currents (EPSCs) observed during neurotransmission at excitatory synapses.151,152
Pharmacology
AMPA receptors are responsible for most of the rapid excitatory neurotransmission within the vertebrate CNS. When compared to NMDA receptors, AMPA receptors have a relatively low affinity for glutamate, the endogenous amino acid that represents the most likely candidate in mediating neurotransmission at both these receptors.117 In addition to AMPA and glutamate, AMPA receptors can be activated following the binding of quisqualic acid, derivatives of willardiine, and natural toxins such as domoic acid. However, as mentioned earlier, the most potent selective agonist for this class of EAA receptor is AMPA67a. As noted earlier, binding of agonists to AMPA receptors often results in various degrees of desensitization, and the desensitization observed appears to be agonist-specific. Little to no desensitization occurs when a partial agonist, such as kainate, is used to induce a current. However, AMPA, quisqualic acid, glutamate, and many other full agonists result in a desensitizing current at this receptor.
Both competitive and noncompetitive antagonists of AMPA receptors have been described. Competitive antagonists of this receptor include 5-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and other analogs of the quinoxalinedione family such as 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo- benzo[f]quinoxaline-7-sulfona- mide (NBQX), DNQX, and 1,4,7,8,9,10-hexahydro-9-methyl-6-nitropyride[3,4-f]quinoxaline-2,3-dione (PNQX).60 This family of antagonists has limited utility in discriminating between AMPA and kainate receptors. Fortunately, noncompetitive antagonists that have a sufficiently higher affinity for AMPA than kainate receptors have been developed; 2,3-benzodiazapines, such as GYKI 52466 and 53655, are relatively selective for AMPA receptors and have allowed for the functional examination of kainate receptors (see below).69
Regulation of AMPA Receptor Subunit Expression and Function
Anatomic Distribution.
The anatomic distribution of AMPA receptors in the CNS has been determined by in situ hybridization, receptor autoradiography, and immunocyto-chemistry.69 These receptors are widely present in projection neurons and interneurons throughout the brain, although regional differences exist in the relative amounts of each of the receptor subunits. For example, whereas GluR1, GluR2, and GluR3 are rather ubiquitously expressed throughout the CNS, GluR4 expression is limited to select regions of the thalamus and cerebellum. In addition, whereas principal neurons utilize AMPA receptors including the GluR2 subunit, interneurons are more likely to express AMPA receptors lacking GluR2 and are thus permeable to Ca2+. AMPA receptors are thought to be located primarily postsynaptically, although some evidence suggests that presynaptic AMPA receptors are present in some neurons and can influence neurotransmitter release.
In addition to neurons, AMPA receptors are also found in glia, where they are thought to be able to sense nearby neuronal activity.156 With regards to epilepsy, the functional properties of these receptors may be modified by changes in the expression levels of individual subunits and/or their pre- and post-translational modifications. For example, it has been demonstrated that GluR1 receptors expressed in hippocampal astrocytes have an elevated flip-to-flop ratio in tissue from humans with pharmacoresistent TLE.135,136 This increase in the flip isoform could result in receptors with slower desensitization and enhanced depolarizations in astrocytes.
Developmental Regulation.
GluR1, GluR2, and GluR3 are all present and expressed at birth in the rat, whereas the GluR4 subunit is not expressed until approximately postnatal day 14. There is considerable developmental regulation of the splice variant forms of the AMPA receptor, and these changes over time can dramatically impact the function of the receptor and ultimately the excitability of the neuron.102 In general, in the adult animal, most AMPA receptors contain the flop form of the receptor subunits. This results in receptors that are generally impermeant to calcium and desensitize rapidly. However, in the young brain, a greater flip-to-flop ratio is present, which results in receptors that are more permeant to calcium and open for longer durations. This contributes greatly to the hyperexcitability observed in the young brain.
Trafficking and Associated Proteins.
Interestingly, it is thought that AMPA receptors are not initially present at excitatory synapses, although NMDA receptors are present at postsynaptic sites at birth. Furthermore, transcription as well
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as insertion of AMPA receptors into postsynaptic sites is tightly regulated and, for some forms of the receptor, is activity dependent. Recent work has dramatically increased the understanding of AMPA receptor trafficking at synapses, and the reader is encouraged to see some excellent recent reviews on this extensive topic.111,116
Briefly, AMPA receptors are assembled in the endoplasmic reticulum, transported through the Golgi, and targeted to the dendrites. The exact mechanisms whereby the receptors are targeted to dendrites and delivered there are currently under investigation. However, because AMPA receptors lack motor components, it is believed that associated proteins are involved in propelling the receptors along cytoskeletal tracks to the dendrites. For GluR2 and GluR3 receptor subunits, interactions with the C-terminus with glutamate receptor interacting protein/AMPA binding protein (GRIP1/ABP) is thought to be necessary for proper dendritic delivery, whereas the interaction of the C-termini of the GluR1 and GluR4 receptors with protein 4.1N seems to be essential for proper delivery of these subunits.16,49,111,138 Although cytoplasmic vesicles are responsible for initial delivery of AMPA receptors, it is unclear whether they deliver them to the postsynaptic or extrasynaptic sites. Indeed, a number of studies indicate that extrasynaptic receptors are free to diffuse to synaptic sites, where they are then anchored in place by a number of scaffolding proteins.
Once at the dendrite, GluR2- and GluR3-containing receptors are free to rapidly cycle between the postsynaptic sites and intracellular compartments constitutively in an activity-independent fashion. Thus, it is thought that these receptors help to maintain a constant level of receptors at the synapse. In contrast, AMPA receptors containing GluR1 and GluR4 subunits are tightly regulated at the synapse in an NMDA- and activity-dependent fashion. It is believed that this activity-dependent regulation of receptor number at the synapse results in both LTP and LTD (see Chapter 35).
Critical to the ability of AMPA receptors to be inserted into the postsynaptic membrane is the presence of the transmembrane AMPA receptor regulatory proteins, or TARPs. These auxiliary proteins have been found to be important for the selective delivery of AMPA receptors to extrasynaptic regions. In addition, TARPs have now been shown to regulate the activity of AMPA receptors. For example, the first TARP to be examined, stargazin, has been shown to increase the affinity for glutamate at the AMPA receptor and also decrease desensitization and deactivation rates.121,134,153 An interesting aside to this story is that the stargazin gene has been implicated in absence seizures observed in the stargazer mouse, although the seizures appear to be linked to the proteins’ interaction with voltage-gated calcium channels in the thalamus.82,83
Different AMPA receptor subunits combine with different combinations of auxiliary proteins that can oversee a myriad of functions of AMPA receptors. In general, the associated proteins fall into one of two categories: PDZ domain–containing proteins and non-PDZ domain–containing proteins. A thorough description of all associated proteins is well beyond the scope of this chapter, and the reader is referred to several recent reviews.116 However, as we learn more about the assembly, targeting, and regulation of function of AMPA receptors, a number of potential therapeutic targets for the treatment of a variety of seizure disorders will no doubt emerge.
AMPA Receptors and Seizures
Clearly, excitatory synaptic transmission is involved in many aspects of synchronization and seizure generation, and there is no doubt that AMPA receptor number and function are critically involved in these mechanisms. Not only are there alterations in excitatory circuits in some forms of epilepsy (most notably mossy fiber sprouting in TLE), but a number of studies have demonstrated that following seizures, changes occur in a number of cell types with regards to the type of AMPA receptor subunits that are expressed. Changes in subunit expression have been observed in both animal models of epilepsy as well as in human epilepsy.37,43,57,61,90,122,131,143 Clearly, these alterations in subunit expression have important ramifications with respect to the function and regulation of excitatory synaptic transmission, and these alterations are just beginning to be understood at the circuit level. Many of these changes in excitatory synaptic transmission are addressed in a number of other chapters in this book and will not be elaborated upon here.
Kainate Receptors
Molecular Biology
Cloning studies have revealed the existence of five kainate receptor (KAR) subunits: The low-affinity subunits GluR5, -6, and -7, and the high-affinity subunits KA1 and KA2. (This topic has been reviewed.)42,80 Multiple alternative splice variants have been identified for GluR5 through GluR7. Additionally, post-transcriptional editing occurs in GluR5 and GluR6 at the glutamine/arginine (Q/R) site, but this does not occur in the GluR7, KA1, or KA2 subunits. GluR5 through GluR7 can form functional homomeric KARs in expression systems, whereas the KA1 andKA2 subunits cannot. However, KA1 and KA2 subunits can assemble with GluR5, -6, and -7 to form functional heteromeric receptors. Clearly, this inherent molecular diversity can lead to the assembly of a sizeable number of different KARs with distinct stoichiometries. As was the case for AMPA receptors, subunit assembly can dictate the functional properties of the resulting receptor-gated ion channels, including permeability, conductance, and pharmacology. For example, homomeric assemblies of GluR5 or GluR6 that possess an arginine at the Q/R site are functionally different from receptors composed of subunits possessing a glutamine.10 These edited, arginine-containing receptors have a reduced calcium permeability, a linear or slightly outward rectifying current-voltage relationship instead of an inward or double rectifying relationship, a single low conductance state as compared with multiple conductance states, and an increased chloride permeability.
Electrophysiology
Postsynaptic Kainate Receptors.
Functional postsynaptic KARs are present in a variety of cell types. Examples include cerebellar granule cells and Golgi cells18,140; retinal bipolar cells40; neurons of the superficial dorsal horn,84 lateral superior olive,158 and motor and somatosensory cortex2,45,71; and a variety of neurons in the hippocampus and amygdala.22,31,32,52,53,54,58,127,157,160 As originally described in CA3 neurons of the hippocampus, KAR-mediated EPSCs are defined as being resistant to inhibition by the AMPA receptor-selective 2,3-benzodiazepine GYKI 53655 (or GYKI 52466), but sensitive to inhibition by CNQX.22 Furthermore, KAR-mediated EPSCs are smaller than their AMPA receptor-mediated counterparts, have significantly slower rise and decay kinetics, and are not potentiated by cyclothiazide.22,157 Even though the KAR contribution to combined AMPA/kainate-mediated EPSCs is relatively small, postsynaptic KARs participate in synaptic transmission and may even be segregated to their own synapses.31 Data using glutamate uptake blockers suggests that the KARs’ slow kinetics are due to intrinsic characteristics18,71 and may impose unique integrative properties to neurons.53
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Presynaptic Kainate Receptors.
Presynaptic KARs have been found to modulate the release of glutamate at a variety of synapses in the CNS and peripheral nervous system (PNS).24,29,55,65,68,70,128,132,133 One of the best studied examples of this is the mossy fiber–CA3 synapse in the hippocampus. At this synapse, presynaptic KARs modulate glutamate release in a bidirectional manner; low KAR agonist concentrations in the nM range increase glutamate release, whereas larger concentrations in the μM range depress the synaptic response. Furthermore, these kainate autoreceptors may sense synaptically released glutamate and play a role in frequency-dependent facilitation.29,75,133 The hippocampal CA3-CA1 is another excitatory synapse modulated by presynaptic KARs. KAR agonist application reduces glutamate release at this synapse by metabotropically inhibiting calcium influx at the terminal.24,29,55 Depolarization of the presynaptic terminals is not necessary for the reduction in glutamate release. This appears to be in contrast to the actions of presynaptic KARs at the mossy fiber–CA3 synapse. This has led some to suggest that modulation of transmitter release by KARs could obey different mechanisms and rules at different synapses.78
Presynaptic KARs have also been found to modulate the release of γ-aminobutyric acid (GABA).3,9,14,30,62,85,99,109,125,126,127,137 KAR agonists depress evoked inhibitory postsynaptic currents (IPSCs) and reduce the frequency of miniature IPSCs as recorded in CA1 PYR neurons of the hippocampus.125 Pertussis toxin can prevent this effect, which suggests that depression of GABA release at this synapse may occur via presynaptic KARs acting through a G-protein–coupled cellular cascade.126 However, KARs do not always act to depress the release of GABA. In the CA1 interneurons of the hippocampus, activation of a separate population of KARs that are likely to be localized to the soma or axon can increase spontaneous GABA release by increasing action potential firing frequency.32,52,54,106,127 Additionally, the activation of presynaptic KARs at synapses between inhibitory interneurons enhances GABA release.30 Furthermore, presynaptic KARs have been found to exert a concentration-dependent bidirectional control of GABA release in the rat amygdala.15 This effect is similar to the aforementioned bidirectional control of glutamate release. These effects of presynaptic KARs on GABA release can be mediated by glutamate released from neighboring excitatory terminals under normal physiologic conditions.99 Taken together, the control of GABA release by KARs may be heterogeneous, again ultimately depending on the properties of the GABA-releasing synapse.78
Pharmacology
The distinction between AMPA and kainate receptors was initially somewhat blurred because both AMPA and KA can activate both types of receptors. However, there are differences in the potency of each agonist at the different receptor subtypes. Whereas the order of agonist potency at AMPA receptors is: Quisqualate > domoic acid ∼AMPA > glutamate > KA, the order for at least some molecular forms of the kainate receptor is: Domoic acid > KA > glutamate > AMPA.
Advances in the development of AMPA and KAR selective antagonists, along with the development of KAR knockout mice, have recently and dramatically increased our understanding of the structure, function, regulation, and pharmacology of these subtypes of iGluRs. In particular, the 2,3-benzodiazepines have been found to be fairly selective for AMPA receptors, and the use of these compounds have helped to reveal the functional expression of KARs on a variety of neuronal cell types. In addition, a number of decahydroxyisoquinoline carboxylate molecules have recently been developed and serve as subunit-selective KAR antagonists. However, these antagonists, (e.g., LY382884 and LY294486) are somewhat selective within the KAR family and mostly block GluR5 subunits. Thus, their utility is somewhat limited to those receptors containing the GluR5 subunit. With regard to epilepsy, a novel anticonvulsant, topiramate, in addition to its other actions on GABA receptors and sodium channels, has been found to effectively block GluR5-containing receptors in the amygdala.58
Many neurons that are subject to cell death following KA-induced status epilepticus also have an abundance of postsynaptic KA receptors. Perhaps the most studied synapse to date in this regard is the mossy fiber–CA3 synapse of the hippocampus. CA3 pyramidal cells are highly susceptible to seizure-induced cell death in human and animal models of TLE, and have a prominent postsynaptic KAR component to the EPSC. Additionally, mossy fiber also contains presynaptic KARs. Activation of these receptors can enhance glutamate release and further contribute to excitotoxicity of CA3 cells during periods of excessive activation, as seen during seizure activity. In addition, knockout mice with targeted deletions of the GluR6 subunit are not as susceptible to the deleterious effects of kainate.105 The CA3 neurons have a greatly reduced sensitivity to the exogenous application of kainate, and the mice are resistant to systemic KA-induced seizures and do not exhibit the same cell death patterns or astrogliosis as the littermate controls. Therefore, it is becoming increasingly clear that KA receptors play an important role in epilepsy.
Regulation of KA Receptor Subunit Expression
Anatomic Distribution.
In situ hybridization and immunohistochemical studies have led to the discovery of different distributions throughout the brain for mRNA encoding GluR5 through GluR7. In contrast to GluR5 and -6, GluR7 is not found in most of the hippocampus, although it has been found in the granule cells of the dentate gyrus.11,12,46 GluR7 mRNA is also quite abundant in the caudate-putamen, but GluR5 is absent from this region. Of particular interest is the finding that mRNA for both GluR6 and -7 is present in high abundance in brain regions that have been found to be profoundly sensitive to destruction following KA treatment. These areas include the hippocampus, cortex, and reticular thalamic regions.
KA1 is expressed at high levels in only CA3 pyramidal cells and dentate granule cells, whereas KA2 is found in virtually all brain regions. Some evidence supports the hypothesis that the KA2 receptor is co-expressed in some areas with GluR6 and -5, and that KA1 may be coexpressed with GluR6 in the hippocampus.
KARs have been found at both postsynaptic and presynaptic locations. At many postsynaptic sites, KARs have been found to contribute substantially to the overall EPSC, thus suggesting that these receptors are colocalized with both AMPA and NMDA receptors. Activation of KARs at presynaptic sites can regulate neurotransmitter release. Activation of the receptor can open the ion channels as well as signal the G-protein, and it has recently been shown that the KA2 subunit is necessary for the G-protein–mediated effects of receptor activation at the mossy fiber–CA3 synapse.130
Developmental Regulation.
Protein for all five KAR subunits has been identified as early as embryonic day (E)14 in the rat brain, and in situ hybridization studies have demonstrated that each of the subunits of the KAR can undergo specific changes in expression levels throughout the brain over the course of development. There is widespread and heterogeneous distribution of the receptor subunits in the adult animal, and the stoichiometry of the receptors in individual cell types is diverse and still under investigation. The GluR5 subunit is expressed at lower levels in the adult brain than in the young animal, and is ultimately found in dorsal root ganglion cells, the septum, subiculum, and a variety of cortical regions.
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The GluR6 subunit is found at its highest levels in the cingulate cortex, granule cells, and CA3 and CA1 pyramidal cells in the hippocampus. GluR7 subunit expression also decreases throughout the course of development, but can be found in the striatum and throughout the cortex and hippocampus. KA1 subunit expression also decreases throughout development and is found ultimately in the CA3 pyramidal cells and subiculum. Finally, KA2 is highly expressed throughout the brain throughout development.77
At thalamocortical synapses, postsynaptic KARs are present early on in development, whereas postsynaptic AMPA receptors develop a little later and ultimately comprise the majority of thalamocortical synapses after postnatal day (P)7.8 KARs have also been found on migrating axons, and the activation of these presynaptic receptors can either increase or decrease axonal motility, depending on the concentration of kainate.77 Therefore, early expression of presynaptic KARs may have functions other than the regulation of transmitter release.
Trafficking and Associated Proteins.
Following assembly of dimers in the endoplasmic reticulum (ER), KARs are sorted and delivered to various locations within the cell. KA2 and GluR5c will remain in the ER unless paired with other subunits due to an ER retention sequence on the subunit. The C-termini of many of the KARs have PDZ-domain binding sites, which suggests that PDZ proteins such as PSD-95, GRIP/ABP, and protein interacting with C kinase 1 (PICK1) may also be involved in trafficking of these receptors to the plasma membrane and postsynaptic sites. GluR6a, GluR5b, and GluR5c contain PDZ-binding domains and, although deletion of that portion of the C-terminal does not interfere with the delivery of the receptors to the plasma membrane, it does prevent the proper insertion into the synapse.79
KA Receptors and Seizure Activity
Many iGluR subunits have been found to be altered in specific cell types and in selective brain regions from patients with epilepsy. Therefore, it comes as no surprise that this has been shown to be the case for KARs as well. For example, Kortenbruck and colleagues have demonstrated that there is a significantly increased editing efficiency at the Q/R site for both GluR5 and -6 receptors in patients with TLE.74
Recent work from Ben-Ari’s laboratory48 demonstrated that mossy fiber sprouting in the KA model of TLE results in excitatory synapses in granule cells that utilize KARs, a situation not found in the control, unsprouted granule cells. It is not clear what role in seizure generation these new synapses play, but nonetheless, the new appearance of postsynaptic KARs in pathophysiology further links these receptors to epilepsy.
NMDA Receptors
Molecular Biology
As with the non-NMDA receptors, cloning of a variety of NMDA receptor subunits has revealed a great diversity of receptors. Three subfamilies of NMDA receptors have been identified: NR1, -2, and -3. Eight splice variants of the NR1 receptor (with the presence of three inserts) have been identified, whereas NR2 has four separate subunits (A–D) encoded by four separate genes.59 Two subunits of the NR3 family of NMDA receptors have been identified and found to be expressed in the CNS: NR3A and NR3B.25,146
Homomeric channels formed from the expression of NR1 mRNA are fully functional, having the typical pharmacology of NMDA receptors. That is, they require the presence of glycine for activation, and a voltage-sensitive block by extracellular magnesium ions (Mg2+) occurs. However, the currents observed from homomeric channels are quite small; this has been interpreted to mean that native receptors likely have additional subunits.41,103
Unlike homomeric NR1 receptors, homomeric NR2 receptors do not form functional ion channels. When each of the four NR2 receptors, A–D, are individually co-expressed with the NMDA receptor (NMDR)-1 receptor, functional channels are observed with large conductances and appropriate pharmacology. Variations in both NR1 and -2 subunits have profound effects on NMDA receptor pharmacology and physiology. For example, one splice variant of NR1 confers sensitivity to polyamines. In addition, heteromeric receptors are sensitive only to the stimulating effect of polyamines if they are composed of NR1A (lacking the N-terminal insertion) and NR2B.161 Similarly, sensitivity to the coagonist effects of glycine and Mg2+ are quite subtype-specific. These factors could have great implications in considering the roles of NMDA receptors in epileptogenesis and in trying to target these receptors for the development of new antiepileptic drugs.
Expression studies in human embryonic kidney (HEK)-293 cells have demonstrated that the NR3A subunit requires the expression of the NR1a subunit for proper assembly and insertion into the membrane. In addition, the presence of the NR3A subunit in combination with the NR1 and NR2A subunit results in a decrease in the single-channel conductance of the NMDA receptor.25,36,118,146 Consistent with this finding, studies in mice lacking the NR3A gene have demonstrated that whole-cell currents induced by the exogenous application of NMDA are increased. In addition, mice lacking the NR3A subunit were also found to have an increase in dendritic spine density in cortical neurons, suggesting that the NR3 subunit can play role in the development of postsynaptic structures.36
Even less is known about the NR3B subunit, which has only recently been cloned.112 This subunit is expressed in motor neurons located in the spinal cord and some brainstem nuclei. Functional channels containing this subunit occur only when both the NR1 and NR2a subunits are expressed. In a manner similar to NR3A, expression of NR3B results in a decreased conductance through the NMDA receptor.112 Thus it would appear that the presence of either NR3 subunit will downregulate current flow through the NMDA receptor-gated ion channel. It is currently unknown whether the NR3 receptor subunits are expressed at native synapses.
Electrophysiology
At hyperpolarized membrane potentials, activation of the NMDA receptor does not result in current flow through the channel. This is because, at hyperpolarized potentials, extracellular Mg2+ will block the channel.114 However, at more depolarized potentials, Mg2+ will be expelled from the channel, and both monovalent and divalent cations (most notably, calcium), can flow through the channel. The permeability of the channel to calcium underlies the great interest in this EAA receptor. The entry of calcium through this channel signals a biochemical cascade, resulting in the development of both LTP and LTD at many synapses (see Chapter 35). The increasing activation of the NMDA channel at depolarized membrane potentials serves as a positive feedback mechanism or amplification mechanism at excitatory synapses. As a postsynaptic cell is depolarized, more current will flow through the NMDA receptor–channel and, therefore, more depolarization will result.
The behavior of the activated NMDA receptor–channel complex differs dramatically from that of the non-NMDA receptors. Activation of the channel is much slower, with the time to the peak current being often tens of milliseconds. Desensitization at NMDA receptors during the exogenous application of agonist takes several hundred milliseconds to develop, whereas desensitization at AMPA receptors occurs within
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5 to 10 msec. The mechanism of desensitization of this receptor (and the determination of whether the receptor desensitizes at all during synaptic events) has been controversial. Desensitization has been attributed to the absence of glycine, such that when glycine is present in high concentrations, desensitization is prevented.94 Other evidence, however, suggests that glycine plays no role in desensitization.63 In addition, a calcium-dependent desensitization has also been described.26
Another difference between non-NMDA and NMDA receptors is the voltage-sensitive block of Mg2+ at the NMDA receptor. The IV relationship of NMDA receptors has a region of negative slope resistance at hyperpolarized potentials, whereas the IV relationship for non-NMDA receptors is linear. In addition, single-channel experiments have revealed that once agonist has bound to the NMDA receptor, the channel can open and close repeatedly for up to several hundred milliseconds, resulting in long-lasting currents.81 Single-channel experiments have also revealed that the primary conductance state for NMDA channels is approximately 50 pS, although transitions to lower conductance states have been observed.34,35
Pharmacology
The NMDA receptor has been studied extensively, especially once it was determined that activation of this EAA receptor underlies different forms of synaptic plasticity in a number of systems. Agonists at the NMDA receptor include NMDA, glutamate, and a variety of other EAAs. As with AMPA and kainate receptors, NMDA receptors possess two agonist-binding sites.27 Specific antagonists at the glutamate-binding site include DL-2-amino-5-phosphonovalerate (APV) and its family, as well as 3-([±]-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and its structurally related family. Of particular interest to the NMDA receptors is the fact that it is the only EAA receptor that has an absolute requirement for a coagonist, glycine.64,72 If the glycine site on the receptor is blocked or unoccupied, binding of glutamate to the receptor will not result in the channel opening. In addition, it seems that, at least in adult rat forebrain, the glycine site of the NMDA receptor is not always saturated, depending on the subunits expressed and the location of the synapse in question.23,159 Therefore, regulation of glycine concentrations may be critical to the regulation of excitatory synapses. In addition to its coagonist requirement, the NMDA receptor has been shown to be modulated by Mg2+, H+, Zn2+, polyamines, steroids, and an oxidation–reduction site.114,144,150,161 Modulation at all these sites represent potential therapeutic targets for the symptomatic treatment of epilepsy.
It was hoped that novel anticonvulsants could be developed to selectively target subunits of NMDA receptors. However, NMDA receptor antagonists are not generally well tolerated, exhibiting a number of adverse effects. Of the newer-generation anticonvulsants, only felbamate has been found to partially block NMDA receptors. However, felbamate is a broad-spectrum compound with multiple modes of action, so it is not felt that the NMDA antagonism can directly explain the efficacy of felbamate.
Regulation of NMDA Receptor Subunit Expression
Anatomic Distribution and Cellular Localization.
In situ hybridization studies have demonstrated that mRNA encoding the NR1 subunit is expressed in almost all neurons in the CNS, although the individual splice variants tend to be more localized.101,103 However, the various NR2 subunits (A–D) are more differentially localized to specific brain regions. For example, the NR2A and -2B subunits are highly expressed in cortical and hippocampal regions, whereas the NR2C subunit is not expressed in these regions. The NR2D subunit is preferentially expressed in olfactory bulb and lower brainstem regions, whereas NR2C is found in the cerebellar granule cell layer.101
Developmental Regulation.
Although the NR1 subunit is ubiquitously present at birth, considerable developmental regulation of NR2 subunits has been described. In rats, the NR2B receptor subunit is present at birth, whereas the NR2A subunit is not expressed until sometime after the second postnatal week. The NR3A subunit has also been shown to be developmentally regulated. Expression of this subunit is high throughout the rat brain during the first few weeks of postnatal life, although in the adult animal, expression occurs only within specific nuclei of the thalamus, amygdala, and lateral olfactory tract.25,146
Trafficking and Associated Proteins.
Tremendous advances have recently been made in our understanding of the regulation of NMDA receptor trafficking and, not surprisingly, many of the same basic processes in play for AMPA and KARs are involved in trafficking NMDA receptors as well. Following assembly in the ER, proteins with PDZ-domain binding sites interact with the NR2 subunits to traffic the receptor to the membrane. In particular, PSD-95 is thought to bind the NMDA receptor and, through an interaction with kinesin, deliver the assembled receptors to the membrane. Delivery of the receptor appears to be NR2 subunit–dependent, with NR2B subunit–containing receptors delivered and inserted to extrasynaptic regions and NR2A-containing receptors delivered and inserted into the synapse. NR2B-containing receptors are free to diffuse to the synapse as needed, and the rate of exocytosis and endocytosis of these receptors is substantially higher than for receptors containing NR2A subunits.123
Although a vast number of proteins have been identified that directly interact with the NMDA receptor, perhaps one of the most important of the associated proteins is calmodulin-dependent protein kinase II (CamKII). Activation of this kinase is critically important for long-term plasticity to occur at excitatory synapses, and it is directly linked to signaling mechanisms involved in regulating AMPA receptor number at the synapse. The regulation of second-messenger signals subsequent to activation of NMDA receptors and Ca2+ influx is continuing to be studied with great interest, and future therapies for seizure disorders may ultimately involve the regulation of proteins associated with iGluRs, rather than direct modulation of the receptor–ion channel complexes.
NMDA Receptors and Seizure Activity
The importance in NMDA receptors for the initiation of long-term changes in various models of synaptic plasticity, along with the ability of NMDA antagonists to block seizure activity in many animal models, has led to the suggestion that excessive activation of these receptors can underlie seizure generation. In addition, the presence of NR2B subunits at synaptic sites can lead to prolonged EPSPs with substantial calcium influx, contributing to hyperexcitability in the developing brain. Therefore, the role of the NMDA receptor in epilepsy has been extensively explored.
Recently, several groups have identified a number of changes in NMDA receptor expression and function in human tissue resected from patients with cortical dysplasia. Alterations in NMDA receptors have also been identified in several animal models of cortical malformations, leading to the hypothesis that, in some cases, altered excitatory synaptic function in these cortical circuits could contribute to the observed hyperexcitability.4,21,33,107 Likewise, a number of alterations in NMDA receptor expression and function have been identified following kindling and in resected human tissue from patients with TLE. How these changes ultimately result in seizure activity remains to be determined—indeed, whether these changes are either compensatory or contributory still must be established. However, future work will undoubtedly contribute to our understanding of the role of the NMDA receptors to seizure activity.
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Metabotropic Excitatory Amino Acid Receptors
The EAAs are also capable of activating a group of receptors that are coupled via second-messenger systems to biochemical pathways and ion channels. These have been called metabotropic glutamate receptors (mGluRs). Based on sequence homology, coupling to different second-messenger systems, and the pharmacology of presently available agonists and antagonists, three separate groups of mGluRs have been established: Groups I, II, and III. These receptors, unlike their inotropic counterparts, are not comprised of subunits that form an integral ion channel; instead, they are comprised of polypeptides that have a putative seven-transmembrane spanning domain with a large extracellular NH2 terminal region. When an agonist binds to the mGluRs, activation of a variety of G-proteins occurs. This G-protein–coupled activation then results in a diverse biochemical cascade that can result in the modulation of a variety of cellular functions, such as current flow through voltage-gated ion channels. Within the three groups of receptors, eight subtypes of the mGluRs have been cloned, and these correspond to a novel gene family of G-protein–coupled receptors.59,110,113 In addition, a number of splice variants have been identified for mGluR1, -4, -5, -6, -7, and -8, leading to a great diversity of potential mGluRs.
Activation of this class of glutamate receptors has been implicated in a variety of CNS functions, including different forms of synaptic plasticity and excitotoxicity. However, until recently, mGluRs have been difficult to study due to the overall lack of and/or availability of specific receptor antagonists and agonists. As was the case for iGluRs, the physiologic functions of the mGluRs are beginning to be deciphered as transgenic animals become available.
This section summarizes what is presently known concerning the pharmacology, anatomic distribution, and role of the three groups of these G-protein–coupled EAA receptors in synaptic transmission, plasticity, and epilepsy. However, for more in-depth coverage of these topics, the reader is encouraged to see some excellent recent reviews.69,113
Group I mGluRs
Group I receptors include the mGluR1 and mGluR5 receptors. The mGluR1 receptor is further characterized by the existence of six splice variants; there are two splice variants for the mGluR5 receptor. Selective agonists, with the ranking of the relative potency, include quisqualate > glutamate > ibotenate > trans-1-aminocyclopentane-1,3-dicarboxylate (tACPD).59 Upon binding of the ligand to the receptor, inositol triphosphate (IP3) and diacylglycerol (DAG) formation is increased, intracellular calcium is mobilized, and arachidonic acid is released. The G-proteins that couple the receptor to the effector mechanisms are pertussis toxin–sensitive for mGluR1.1,5,69
In situ hybridization studies have revealed that the mRNA encoding for Group I mGluRs is highly abundant in the CA2 and CA3 cell layers of the hippocampus. However, although mRNA for mGluR1 is found to be highly expressed in Pur- kinje cells of the cerebellum, mGluR5 is not present at all in these cells. Likewise, although CA1 cells of the hippocampus have mGluR5 mRNA, these same neurons have virtually no detectable mRNA for mGluR1.1,89 Although both mGluR1 and -5 are coupled to the same effector system, only activation of mGluR5 results in the induction of hyperexcitability and epileptiform activity in hippocampal brain slices. However, activation of both mGluR1 and -5 is required to maintain this electrographic behavior. It is intriguing to note that antago-nists of both mGluR1 and -5 can act as anticonvulsants100 in a variety of animal models as well.96,97,98
Group II mGluRs
Group II mGluRs include the mGluR2, -3, and -8 subtypes of the receptor family. Unlike Group 1 receptors, activation of Group II mGluRs results in the suppression of forskolin-stimulated cyclic adenosine monophosphate (cAMP) accumulation.148,149 The agonists, in the relative order of potency for this group, include: Glutamate > tACPD = ibotenate > quisqualate.59 The actions of all members of this group are blocked by pertussis toxin. Activation of receptors in this group, as well as those of Group III, often results in a decrease in neurotransmission at both glutamatergic and GABAergic synapses. A rather specific antagonist at both Group II and Group III receptors has been identified: +-α-methyl-4-carboxyphenyl-glycine (MCPG).44 This antagonist can block the decrease in neurotransmission observed in the presence of tACPD.87 Although somewhat controversial, it is believed that activation of tACPD-sensitive receptors may play a role in the development of both LTP and LTD in various regions of the brain.
In situ hybridization studies have determined that the mGluR2 receptor is abundantly expressed in Golgi cells of the cerebellum and granule cells in the accessory olfactory bulb. This receptor type is also abundant in the neocortex and hippocampus. The mGluR3 mRNA is also highly expressed in the neocortex and hippocampus.149 In a developmental model of epilepsy, recent work using a novel Group II agonist, (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate (2R,4R-APDC), has demonstrated that the activation of these receptors can be both neuroprotective and anticonvulsant.149
Group III mGluRs
The mGluRs considered members of Group III include mGluR4, -6, and -7.69,108 As with the activation of Group II receptors, activation of those in this group results in a reduction of forskolin-stimulated increase in cAMP production.69 However, these receptors are specifically activated by the selective agonist L-2-amino-4-phosphonobutyrate (L-AP4). These receptors are also activated following binding of both glutamate and tACPD. MCPG acts as a potent antagonist at these receptors. mGluR4-mediated activation of G-proteins is blocked by pertussis toxin, but mGluR6-mediated activation is not.
mGluR6 mRNA is found exclusively in the retina, and evidence suggests that mGluR4 is present in both the retina and cerebellum. mGluR7 is widely distributed throughout the brain. mGluR6 is involved in signal transduction from photoreceptors to on-bipolar neurons in the retina, whereas mGluR4 and -7 may be involved in regulating neurotransmitter release.115,148 Indeed, recent evidence also suggests that agonists of mGluR4 can also be useful for protection against seizure activity.88
Role of mGluRs in Epileptic Activity
Many, if not all, neurons in the CNS appear to have mGluRs on axon terminals, where they mediate presynaptic modulation. In addition, activation of postsynaptic receptors may cause direct depolarization and modulation of intrinsic currents. Activation of mGluRs most often results in presynaptic inhibition and postsynaptic excitation and, thus, the net effect may be variable, brain site-specific, and may depend on the distribution of the various receptor subtypes and their cellular locations. It is not surprising, therefore, that activation or inhibition of these
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receptors may modulate epileptiform activity. Data suggests that mGluRs may be involved in the transition between interictal and ictal behavior in the amygdala6 and in the maintenance of interictal activity in the hippocampus.95 In the neocortex, mGluR activation may have both suppressive and stimulatory effects, presumably based on different receptor subtypes, and this may also be developmentally regulated.19,20 As more is learned about the pharmacology of these receptors, as subtype-specific agonists and antagonists and as transgenic animals with targeted deletions of the mGluRs become even more available, it is possible that a new class of antiepileptic drug could emerge that would selectively enhance the suppressive effects or inhibit the stimulatory effects of mGluR activation.
Summary and Conclusions
Synaptic excitation plays a critical role in essentially every function that the CNS is designed to perform. Small transient perturbations in the efficacy of excitatory transmission or in the balance between excitation and inhibition can lead to a seizure. Permanent changes in excitatory synaptic efficacy, or changes in local recurrent excitatory circuitry, can lead to a hyperexcitable state that we call epilepsy. The molecular mechanisms that underlie excitation at the biophysical and pharmacologic levels are beginning to be unraveled. Individual AMPA, kainate, and NMDA receptor–channel complexes can be analyzed, and their subunits characterized. Metabotropic glutamate receptors and their associated G-proteins, which appear to serve as modulatory elements at both excitatory and inhibitory synapses, are also being identified. The circuits within which all these receptors play their critical roles are being characterized, and changes that occur in epileptic brains are being identified. Each of these areas holds the potential for developing new strategies either to prevent the development of epileptic circuits or to target highly specific agents to interfere with the development of epileptic events, even if an epileptic propensity exists in an injured tissue.
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