What is GABAergic Inhibition? How Is it Modified in Epilepsy?

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1 Epilepsia, 41(Suppl. 6):S90-S95, 2000 Lippincott Williams & Wilkins, Inc., Baltimore 0 International League Against Epilepsy What is GABAergic Inhibition? How Is it Modified in Epilepsy? C. Bernard, R. Cossart, J. C. Hirsch, M. Esclapez, and Y. Ben-Ari IMSERM U29-INMED, Pare Scientifique de Luminy, Marseille Ckdex, France Summary: A deficit of y-aminobutyric acid-ergic (GABAergic) inhibition is hypothesized to underlie most forms of epilepsy. Although apparently a straightforward and logical hypothesis to test, the search for a deficit of GABAergic inhibition in epileptic tissue has revealed itself to be as difficult as the quest for the Holy Grail. The investigator faces many obstacles, including the multiplicity of GABAergic inhibitory pathways and the multiplicity of variables that characterize the potency of inhibition within each inhibitory pathway. Perhaps more importantly, there seems to be no consensual definition of GABAergic inhibition. The first goal of this review is to try to clarify the notion of GABAergic inhibition. The second goal is to summarize our current knowledge of the various alterations that occur in the GABAergic pathways in temporal lobe epilepsy. Two important features will emerge: (a) according to the variable used to measure GABAergic inhibition, it may appear increased, decreased, or unchanged; and (b) these modifications are brain area- and inhibitory pathway-specific. The possible functional consequences of these alterations are discussed. Key Words: Temporal lobe epilepsy-hippocampus- GAB A-Interneurone. In the adult hippocampus, the output of principal cells (dentate granule cells, CA3 and CA1 pyramidal neurons) is tightly controlled by the activity of y-aminobutyric acid-ergic (GABAergic) interneurons. This control has at least three main components: (a) the activation of postsynaptic GABA receptors counteracts the membrane depolarization induced by excitatory inputs via direct hyperpolarizing or shunt effects; (b) GABA receptormediated synaptic responses can directly block action potential firing (l,2); and (c) interneurons can synchronize the firing of principal neurons during oscillations (3-6). These three effects of GABAergic inhibition ultimately modify the probability of action potential firing in the postsynaptic neuron. In temporal lobe epilepsy (TLE), highly synchronous discharges occur simultaneously in large populations of neurons. Is such abnormal behavior related to a modification of the control of principal cells by GABAergic interneurons? Two nonexclusive hypotheses can be proposed: the ability of inhibition to counterbalance membrane depolarization and action potential firing is decreased, and modifications occur within the interneuronal network to facilitate the synchronized firing of principal cells. Interneurons and principal cells fire synchronously during epileptiform discharges (7,8), but the Address correspondence and reprint requests to Dr. Christophe Bernard at Division of Neuroscience, S700, Baylor College of Medicine, I Baylor Plaza, Houston, TX 77030, U.S.A. cbemard@ 1tp.neusc.bcm. trnc.edu involvement of interneurons in the synchronization of principal cells in chronic epilepsy remains to be investigated. Although a potentially important mechanism to explain epileptogenesis (9), this hypothesis will not be discussed further. The present review focuses on the other hypothesis, i.e., a deficit of inhibition in chronic epilepsy, particularly with regard to the fate of GABA, receptor-mediated inhibition. Because compounds that enhance GABAA receptormediated inhibition are used successfully in controlling some types of epilepsies in humans and because epileptiform activity can be triggered when GABAA receptormediated inhibition is blocked in most brain structures (lo), it is often taken for granted that GABAergic inhibition is decreased in epileptic tissue, although there is some disagreement on this point (1 1,12). However, if A implies B, it does not necessarily mean that B implies A. Obviously, the hypothesis is a valid one, and it has been tested extensively. Before providing some of the most important results related to the fate of inhibition in TLE, it is necessary to ask a critical question: What is GABAergic inhibition? WHAT IS GABAERGIC INHIBITION? The definition of GABAergic inhibition faces three major difficulties. (a) Because inhibition implies the ability to restrain, activation of postsynaptic GABAA receptors should decrease the firing probability of the inhibited neuron. However, the consequences of GABA, receptor activa- S90

2 GABAERGIC INHIBITION S91 tion critically depend on the experimental conditions. According to the concentration gradients of chloride and bicarbonate, the anions that permeate the GABAA ionophore, the activation of GABAA receptors can lead to either a depolarization or a hyperpolarization of the postsynaptic membrane. The depolarizing action of GABA is not limited to neonates (13); it also occurs in the dendrites after intense activation of GABA, receptors (14,15). Even when GABA has a hyperpolarizing action, it can lead to delayed excitatory action via a direct interaction with intrinsic membrane conductances (4). For example, GABA, receptor-mediated hyperpolarization of the membrane could deinactivate Ca2+ channels and secondarily boost excitatory inputs, facilitate back-propagation of action potentials from the soma to the dendrites, and induce abnormal action potential firing in the dendrites (16). Therefore, the first difficulty lies in the fact that inhibition does not seem appropriate to describe a context-dependent concept, i.e., GABA, receptor function. For lack of a better term, we will still use GABAergic inhibition, and for the sake of simplicity in this review, we will consider only the GABA, receptor-mediated hyperpolarizing/ shunt effect. (b) What determines the potency of inhibition, i.e., the level of hyperpolarizing/shunt in the postsynaptic cell? The hyperpolarizinghhunt effect results from the opening of the GABA, ionophore after the fixation of synaptically released GABA on its receptor site. Therein lies the second difficulty in defining GABAergic inhibition. The hyperpolarizing/shunt effect is controlled by a constellation of variables that range from the properties of the GABAergic neurons to those of the GABAergic synapse. Some of these are detailed below. At the end of the line lie the GABAA receptors. Their physiological properties (conductance, kinetics, inactivation) depend on their subunit composition and on the action of intracellular (protein kinases, Ca2+) as well as extracellular (benzodiazepines, barbiturates, steroids, polyvalent cations, ethanol) factors (17). The activation of GABAA receptors usually results from the synaptic release of GABA. Two types of release have been identified; one requires the presence of an action potential in the presynaptic terminal, and the other occurs randomly in an action potential-independent manner (e.g., miniature activity). In both cases, exocytosis of a GABA-containing vesicle is a probable event modulated by the properties of the terminal internal machinery (including the various Ca effectors), the past activity of the terminal, diffusible factors, polyvalent cations, and a very large number of ionotropic and metabotropic receptors for neurotransmitters or neuromodulators located on the presynaptic terminal (18; see also 19,20 for additional references). During steady-state conditions in vitro, miniature activity in CA1 pyramidal cells represents as much as 60% of the GABAergic activity received by principal neuron somata (21,22). The rest (40%) is provided by an action potential-dependent process, e.g., the firing of GABAergic interneurons. Going farther upstream, the amount of activitydependent GABAergic inhibition received by postsynaptic neurons is a function of the number of presynaptic terminals made by a single GABAergic neuron, the number of presynaptic GABAergic neurons, the intrinsic membrane properties of the latter, the distribution/ properties of their various receptor channels, and the distributiordproperties of their presynaptic excitatory and inhibitory terminals. Thus, the number of variables that need to be assessed to describe GABAergic inhibition is truly mind boggling. (c) The third difficulty is attributable to the multiplicity of GABAergic pathways. Each pathway is defined by a specific class of inhibitory neuron with unique morphological, physiological, and functional features (1,20,23,24). Because of this heterogeneity, each subspecific inhibitory pathway should be investigated in isolation, i.e., each of the variables cited in the previous paragraph should be assessed for each subspecific inhibitory pathway. What, then, is GABAergic inhibition? GABAergic inhibition can be defined as a set of variables distributed in multiple inhibitory pathways. Because the values of these variables are continuously changing and interacting, the state of inhibition can only be approached when the system is frozen in a quasi-stable state. Only in this condition can inhibition be compared in two conditions, e.g., in epileptic and control neuronal networks. Unfortunately, this type of approach can only give a partial image of a multidimensional object. Many of these variables have been assessed in human and experimental TLE, and it is now clear that multiple modifications occur at different locations. We will now detail some of the modifications that occur in the various inhibitory pathways, from the source of GABAergic inhibition, the GABAergic interneurons, to the targets, the postsynaptic GABAA receptors. LOSS OF INTERNEURONS IN TLE Numerous studies have consistently reported a loss of GABAergic interneurons in experimental (25-30) as well as in human (31-34) TLE. This loss of inhibitory interneurons should lead to a decreased number of inhibitory synapses on the postsynaptic cells. Ultrastructural studies indicate that the number of perisomatic GABAergic terminals on CA1 pyramidal cells is not modified in the kainic acid and pilocarpine models of TLE before (35) and after spontaneous recurrent seizures have developed (36). Interestingly, in the kainic acid model, a loss of perisomatic parvalbumin- Epilepsia. Val. 41, Suppl. 6, 2000

3 S92 C. BERNARD ET AL. immunoreactive terminals was reported, whereas the number of these terminals around the initial segment of CA1 pyramidal cells remained unchanged (28). These results suggest a transient deafferentation of pyramidal cell somata by GABAergic terminals followed by a reafferentation, implying a reactive synaptogenesis. A transient loss of inhibitory terminals could explain the transient loss of paired pulse inhibition (37). The sprouting of the axon of GABAergic neurons has been reported in another preparation (38); in the hippocampus, it could occur in parallel with the well-documented recovery of excitatory terminals via the sprouting of excitatory axons in TLE (31,3947). GABAergic terminals along the dendrites of principal cells have not been quantified. A massive reorganization is expected along the dendrites because of the clearly identified loss of somatostatin-containing interneurons in TLE (48,49). In the CA1 area, most somatostatinergic interneurons are located in the stratum oriens, where they represent the most prevalent population of GABAergic interneurons (23,50). The extensive axonal arbor of somatostatinergic interneurons forms symmetric synapses preferentially on the distal dendrites of pyramidal cells (51), at the site of perforant path afferences in the lacunosum moleculare. The loss of somatostatinergic interneurons may have important functional consequences, not only because somatostatin has anticonvulsant properties (52,53) but also because of the resulting disinhibition of pyramidal cells. Somatostatinergic interneurons are reliably activated by excitatory inputs (54), they receive a strong excitation from pyramidal cells (55-57), and, in the slice preparation, most of them (SO%) fire spontaneously, thus providing a strong, precise inhibitory barrage at the site of perforant path afferences (our unpublished observations). Because a decrease in the activity of these interneurons allows the direct excitation of CAI pyramidal cells by the temporoammonic pathway (57), their loss would have a direct disinhibitory effect in chronic epilepsy. This issue remains to be investigated. In chronic epilepsy, the fate of other types of GABAergic interneurons containing other peptides or calcium-binding proteins (vasoactive intestinal polypeptide [VIP], cholecystokinin [CCK], calretinin, etc.) has not been addressed. The loss of GABAergic interneurons should logically result in the disinhibition of principal cells. This hypothesis is supported by the decrease in paired-pulse inhibition (a quantity hypothesized to be related to the strength of inhibition) reported in vivo (3738). However, as reported above, paired-pulse inhibition recovers 7 to 8 days after the initial lesion-induced status epilepticus (37), suggesting that the surviving inhibitory pathways can still exert their function. This raises the question of the fate of the surviving GABAergic interneurons in TLE. MODIFICATIONS IN THE SURVIVING INHIBITORY PATHWAYS IN TLE An ultrastructural study indicates that the number of GABAergic and non-gabaergic terminals is not modified in various types of interneurons in TLE, although an increase in the number and length of GABAergic terminals in the perisomatic region of lacunosum moleculare interneurons was reported (59). A similar study performed in the dendrites of the various types of interneurons should give some insight into the reorganization of the distribution of synaptic terminals. These data are now available in control tissue and could be used for comparison (60). What are the properties of the excitatory and inhibitory synapses in the surviving interneurons in TLE? Neither evoked excitatory nor inhibitory responses seem modified in interneurons, despite a transient decrease of the latter in lacunosum moleculare interneurons (61,62). The functional properties of the presynaptic terminals, the distribution and properties of postsynaptic receptors, and their control by extracellular and intracellular factors remain to be investigated. These issues are important to consider because these factors are modified in principal cells in TLE (36,63-65). Is the functioning mode of interneurons modified in TLE? It is now clear that interneurons are not dormant in TLE (66). All of the interneurons recorded in chronically epileptic animals fired bursts of action potentials after stimulation of their excitatory afferents (7,61). More importantly, synchronized epileptiform discharges occur simultaneously in interneurons and pyramidal cells during spontaneous seizures in chronic models of TLE (7) as well as in acute models (8). Epileptiform discharges in interneurons are dependent on the activation of N- methyl-d-aspartate receptors (7), as in pyramidal cells (67), suggesting a reorganization of the excitatory pathways common to principal cells and interneurons. However, many issues remain to be investigated, including the intrinsic membrane properties of the surviving interneurons and the distribution and properties of their excitatory and inhibitory synapses. As mentioned above, principal cells receive a continuous bombardment of inhibitory signals in vitro, part of which (40%) is provided by the firing of interneurons. In control tissue, one-third of the interneuronal population fires spontaneously (22,68-70) at an average frequency of 4.5 Hz (70). In TLE, four-fifths of the interneuronal population fires spontaneously, and the average frequency is increased to 9 Hz (22,70). Therefore, the spontaneous activity of interneurons is increased in TLE. This hyperactivity is dependent on the activation of glutamatergic receptors (our unpublished observations) and seems to be attributable to the increased excitatory drive (>700%) received by interneurons in TLE compared Epilepsia, Vol. 41, SuppE. 6, 2000

4 GABAERGIC INHIBITION s93 with controls (22,70). This glutamate receptordependent hyperactivity is found in all morphologically identified interneurons (22,70). It is possible that the increased excitatory drive reported in interneurons results from the sprouting of the CA1 associational pathway (46,47). In CA1 pyramidal cells, the excitatory drive is increased by 500% in TLE, and it is directly related to the sprouting of the CAl-associated pathway (47). Thus, the modifications that occur within the interneuronal population are complex. On the one hand, the loss of interneurons should logically result in a decreased inhibitory control of principal cells. On the other hand, the hyperexcitability and hyperactivity of the surviving interneurons should result in an increased inhibitory control of principal cells. To determine which of these two phenomena is predominant, it is necessary to measure the amount of inhibition received by the principal cells. GABAERGIC INHIBITION IN PRINCIPAL CELLS IN TLE A large set of variables can describe the activity at a given GABAergic synapse, including the activity of its source (the emitting interneuron), the properties of the presynaptic GABAergic terminal and its control by neuromodulators, and the properties of the postsynaptic GABA, receptors and their control by extracellular and intracellular factors. Because of the heterogeneity of interneuronal types (1,23,24), each set of variables should be assessed for each type of GABAergic synapse thus defined. So far, some of these variables have been characterized using mostly somatic recordings. Because it is not possible to clamp large dendritic structures (71-74), somatic recordings mostly provide information about perisomatic GABAergic synapses, i.e., synapses originating from either basket or chandelier cells (23). These interneurons appear to play a very important role because activation of the perisomatic inhibitory pathway can block action potential firing in principal cells (1) or synchronize their firing (4). The postsynaptic perisomatic GABA, receptors undergo a profound reorganization in TLE. Modification of the GABAA receptor subunits expressed in dentate granule cells (65) results in larger evoked responses to GABA, a decreased sensitivity to zolpidem, and an increased inhibition by Zn2+ (63-65). In parallel, the number of postsynaptic GABAA receptors is increased (75). In CA1 pyramidal cells, the reorganization is different. Although it is not known whether the expression of GABA, receptor subunits is changed in these neurons, GABAA receptor-mediated responses are decreased (36,64) and the effect of clonazepam is reduced (64). Despite the decrease of postsynaptic responses, perisomatic GABA, receptor-mediated responses can still block action potential firing in CAI pyramidal cells (7). A major conclusion from these observations is that the alterations in the GABAergic pathways are area-dependent. Presynaptic terminals also undergo modifications in experimental epilepsy. Perisomatic presynaptic boutons on dentate granule and CA1 pyramidal cells are enlarged (36,75), and the reserve pool of GABA-containing vesicles is depleted by 50% (36). The control of the presynaptic terminals is also altered. Zinc inhibits miniature activity in dentate granule cells (63), whereas the inhibition of GABA release by the activation of GABA, autoreceptors disappears in CA1 pyramidal cells in TLE (76). Finally, miniature activity, which provides 60% of the spontaneous inhibitory drive in controls (77), is decreased by more than 50% in CA1 pyramidal cells in TLE (36). Interestingly, miniature activity is increased in a model of febrile seizure (78) and in a cortical model of postlesional epilepsy (1 1). These observations indicate a profound modification in the function of presynaptic terminals that is area-dependent. However, the probability of release of GABA after an action potential in the presynaptic terminal, possibly the most important factor, has not been quantified. Taking into account the modifications that occur within the various inhibitory pathways (from the interneuron to the postsynaptic GABA, receptor), what is the amount of inhibition received by pyramidal cells? Two functional states should be investigated: steady state (outside epileptiform activity) and transients (during epileptiform activity). During steady state, the amount of inhibition received by CA1 pyramidal cell somata is increased by 50% because of the hyperactivity of perisomatic inhibitory interneurons (22,70), despite the deficit of GABA quanta1 release (36). In CA1 pyramidal cell dendrites, the inhibitory drive is decreased by 35%, possibly because of the loss of interneurons, in particular the somatostatinergic population (79). During transients, although CA1 pyramidal cell somata still receive large GABAergic currents (7), these currents appear downregulated by the large Ca2+ influx that occurs at the same time (80,81). CONCLUSION The major conclusion to be drawn from these observations is a lesson in humility. Each modification of the factors that characterize inhibition is model-, time-, area-, and pathway-dependent. Within one brain region, for one model of epilepsy, at a given time, some modifications will appear as proepileptic and others will appear as antiepileptic. In fact, the number of factors that can be modified is so important that it is impossible to predict the resulting behavior of the neuronal network. An integrative framework is needed, and realistic computer models could prove useful to understanding the Epilepsia, Vol. 41, Suppl. 6, 2000

5 s94 C. BERNARD ET AL. outcome of these modifications. However, as mentioned above, some critical variables still need to be assessed in each subspecific inhibitory pathway. The latter point is particularly important to consider because there exist clear anatomical and functional organizing principles defined by the diverse types of GABAergic neurons and their synapses (20). REFERENCES 1. Miles R, Toth K, GulyPs AI, Hajos N, Freund TF. Differences between somatic and dendritic inhibition in the hippocampus. Neuron 1996; 16% Dvorak-Carbone H, Schuman EM. Patterned activity in stratum lacunosum moleculare inhibits CAI pyramidal neuron firing. J Neurophysiol 1999;82: Buzs6ki G, Horvath Z, Urioste R, Hetke J, Wise K. Highfrequency network oscillation in the hippocampus. Science 1992; 256: Cobb SR, Buhl EH, Halasy K, Paulsen 0, Somogyi P. Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons. Nature 1995;378: Whittington MA, Traub RD, Jefferys JG. Synchronized oscillations in interneuron networks driven by metabotropic glutamate receptor activation. Nature 1995;373: Csicsvari J, Hirase H, Czurko A, Mamiya A, Buzsaki G. Oscillatory coupling of hippocampal pyramidal cells and interneurons in the behaving rat. J Neurosci 1999;19: Esclapez M, Hirsch JC, Khazipov R, Ben-Ari Y, Bernard C. Operative GABAergic inhibition in hippocampal CAI pyramidal neurons in experimental epilepsy. Proc Nut1 Acad Sci USA 1997;94: Velazquez JL, Carlen PL. Synchronization of GABAergic interneuronal networks during seizure-like activity in the rat horizontal hippocampal slice. Eur J Neurosci 1999;11: Avoli M. GABA-mediated synchronous potentials and seizure generation. Epilepsiu 1996;37: Prince DA. Neurophysiology of epilepsy. Annu Rev Neurosci 1978; 1 : Prince DA, Jacobs KM, Salin PA, Hoffman S, Parada I. Chronic focal neocortical epileptogenesis: does disinhibition play a role? Can J Physiol Pharmacol 1997;75: Bush PC, Prince DA, Miller KD. Increased pyramidal excitability and NMDA conductance can explain posttraumatic epileptogenesis without disinhibition: a model. J Neurophysiol 1999;82: Cherubini E, Gaiarsa JL, Ben-Ari Y. GABA: an excitatory transmitter in early postnatal life. Trends Neurosci 1991;14: Andersen P, Dingledine R, Gjerstad L, Langmoen IA, Laursen AM. Two different responses of hippocampal pyramidal cells to application of gamma-amino butyric acid. J Physiol 1980;305: Staley KJ, Soldo BL, Proctor WR. Ionic mechanisms of neuronal excitation by inhibitory GABAA receptors. Science 1995;269: Magee J, Hoffman D, Colbert C, Johnston D. Electrical and calcium signaling in dendrites of hippocampal pyramidal neurons. Annu Rev Physiol 1998;60: Hevers W, Luddens H. The diversity of GABAA receptors: pharmacological and electrophysiological properties of GABAA channel subtypes. Mol Neurobiol 1998;18: MacDermott AB, Role LW, Siegelbaum SA. Presynaptic ionotropic receptors and the control of transmitter release. Annu Rev Neurosci 1999;22: Cossart R, Esclapez M, Hirsch JC, Bernard C, Ben-Ari Y. GluR5 kainate receptors activation in interneurons increases tonic inhibition of pyramidal cells. Nut Neurosci 1998;1: Gupta A, Wang Y, Markram H. Organizing principles for a diversity of GABAergic interneurons and synapses in the neocortex. Science 2000;287: Soltesz I, Smetters DK, Mody I. Tonic inhibition originates from synapses close to the soma. Neuron I995;14: Bernard C, Esclapez M, Hirsch JC, et al. Increased inhibitory GABAergic drive in the soma of CAI pyramidal cells in experimental epilepsy. Soc Neurosci Abstr 1999;29: Freund TF, Buzsfiki G. Interneurons of the hippocampus. Hippocampus 1996;6: Parra P, Gulyas AI, Miles R. How many subtypes of inhibitory cells in the hippocampus? Neuron 1998;20: Ben-Ari Y, Nitecka L, Woodson W, Robain 0, Gho M, Cherubini E. Vulnerabilite preferentielle des interneurones GABAergiques de l hippocampe a l acide kainique. L encephale 1987; 26. Sloviter RS. Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science I987;235: Obenaus A, Esclapez M, Houser CR. Loss of glutamate decarboxylase mrna-containing neurons in the rat dentate gyms following pilocarpine-induced seizures. J Neurosci 1993;13: Best N, Mitchell J, Wheal HV. Ultrastructure of parvalbuminimmunoreactive neurons in the CAI area of the rat hippocampus following a kainic acid injection. Actu Neuropathol 1994;87: Houser CR, Esclapez M. Vulnerability and plasticity of the GABA system in the pilocarpine model of spontaneous recurrent seizures. Epilepsy Res 1996;26: Morin F, Beaulieu C, Lacaille JC. Selective loss of GABA neurons in area CAI of the rat hippocampus after intraventricular kainate. Epilepsy Res 1998;32: DeLanerolle N, Kim J, Robbins R, Spencer D. Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res 1989;495: Robbins RJ, Brines JL, Kim JH, et al. A selective loss of somatostatin in the hippocampus of patients with temporal lobe epilepsy. Ann Neurol 1991;29: Mathern GW, Babb TL, Pretorius JK, Leite JP. Reactive synaptogenesis and neuron densities for neuropeptide Y, somatostatin, and glutamate decarboxylase immunoreactivity in the epileptogenic human fascia dentata. J Neurosci 1995;15: Marco P, Sola R, Alijarde M, Sanchez A, Ramon y Cajal S, De- Felipe J. Inhibitory neurons in the human epileptogenic temporal neocortex: an immunocytochemical study. Brain 1996;119: , 35. Chapman CA, Lacaille JC. Intrinsic theta-frequency membrane potential oscillations in hippocampal CA 1 interneurons of stratum lacunosum-moleculare. J Neurophysiol 1999;81: Hirsch JC, Agassandian C, Merchhn-Pbrez A, et al. Deficit of quanta1 release of GABA in experimental temporal lobe epilepsy. Nut Neurosci 1999;2: Hellier JL, Patrylo PR, Dou P, Nett M, Rose GM, Dudek FE. Assessment of inhibition and epileptiform activity in the septa1 dentate gyrus of freely behaving rats during the first week after kainate treatment. J Neurosci 1999;19: Seil FJ, Drake-Baumann R, Leiman AM, Herndon RM, Tiekotter KL. Morphological correlates of altered neuronal activity in organotypic cerebellar cultures chronically exposed to anti-gaba agents. Dev Brain Res 1994;77: Nadler J, Perry B, Cotman C. Selective reinnervation of hippocampal area CAI and fascia dentate after destruction of CA3-CA4 afferents with kainic acid. Brain Res 1980;182: Nadler J, Perry B, Gentry C, Cotman C. Loss and reacquisition of hippocampal synapses after selective destruction of CA3-CA4 afferents with kainic acid. Brain Res 1980;191: Tauck D, Nadler J. Evidence for functional mossy fiber sprouting in hippocampal formation of kainic acid treated rats. J Neurosci 1985;5: Represa A, Tremblay E, Ben-Ari Y. Kainate binding sites in the hippocampal mossy fibers: localization and plasticity. Neuroscience 1987;20: Phelps S, Mitchell J, Wheal H. Changes to synaptic ultrastructure in field CA1 of the rat hippocampus following intracerebroventricular injection of kainic acid. Neuroscience 1991;40: Cronin J, Obenaus A, Houser CR, Dudek FE. Electrophysiology of dentate granule cells after kainate-induced synaptic reorganization of the mossy fibers. Bruin Res 1992;573:305-10, Epilepsia, Vol. 41, Suppl. 6, 2000

6 GABAERGIC INHIBITION s Represa A, Ben-Ari Y. Kindling is associated with the formation of novel mossy fibre synapses in the CA3 region. Exp Bruin Res 1992;92: Perez Y, Morin F, Jutras I, Beaulieu C, Lacaille J-C. CA1 pyramidal cells in hyperexcitable slices of kainate-treated rats show sprouting of local axon collaterals. Eur J Neurosci 1996;8: Esclapez M, Hirsch JC, Ben-Ari Y, Bernard C. Newly formed excitatory pathways provide a substrate for hyperexcitability in experimental temporal lobe epilepsy. J Comp Neurol 1999;408: Morin F, Beanlieu C, Lacaille JC. Selective loss of GABA neurons in area CA1 of the rat hippocampus after intraventricular kainate. Epilepsy Res 1998;32: Buckmaster PS, Jongen-Relo AL. Highly specific neuron loss preserves lateral inhibitory circuits in the dentate gyrus of kainateinduced epileptic rats. J Neurosci 1999;19: SO. Kosaka T, Wu J-Y, Benoit R. GABAergic neurons containing somatostatin-like immunoreactivity in the rat hippocampus and dentate gyrus. Exp Bruin Res 1988;71: Katona I, Acsady L, Freund TF. Postsynaptic targets of somatostatin-immunoreactive interneurons in the rat hippocampus. Neuroscience 1999;88: Tallent MK, Siggins GR. Somatostatin acts in CA1 and CA3 to reduce hippocampal epileptiform activity. J Neurophysiol 1999; 81 : Vezzani A, Hoyer D. Brain somatostatin: a candidate inhibitory role in seizures and epileptogenesis. Eur J Neurosci 1999;11: Martina M, Vida I, Jonas P. Distal initiation and active propagation of action potentials in interneuron dendrites. Science 2000;287: Lacaille JC, Mueller A, Kunkel D, Schwartzkroin PA. Local circuit interactions between orienslalveus interneurons and CA1 pyramidal cells in hippocampal slices: electrophysiology and morphology. J Neurosci 1987;7: Blasco-lbanez JM, Freund TF. Synaptic input of horizontal interneurons in stratum oriens of the hippocampal CA1 subfield: structural basis of feed-back activation. Eur J Neurosci 1995;7: Maccafeni G, McBain CJ. Passive propagation of LTD to stratum oriens-alveus inhibitory neurons modulates the temporoammonic input to the hippocampal CA1 region. Neuron 1995;15: Sloviter RS. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the dormant basket cell hypothesis and its relevance to temporal lobe epilepsy. Hippocumpus 1991;1: Morin F, Beaulieu C, Lacaille JC. Alterations of perisomatic GABA synapses on hippocampal CA1 inhibitory interneurons and pyramidal cells in the kainate model of epilepsy. Neuroscience 1999;93: Gulyas AI, Megias M, Emri Z, Freund TF. Total number and ratio of excitatory and inhibitory synapses converging onto single intemeurons of different types in the CA1 area of the rat hippocampus. J Neurosci 1999;19: Rempe DA, Bertram EH, Williamson JM, Lothman EW. Interneurons in area CA1 stratum radiatum and stratum oriens remain functionally connected to excitatory synaptic input in chronically epileptic animals. J Neurophysiol 1997;78: Morin F, Beaulieu C, Lacaille J. Cell-specific alterations in synaptic properties of hippocampal CA1 interneurons after kainate treatment. J Neurophysiol 1998;80: Buhl E, Otis T, Mody 1. Zinc-induced collapse of augmented in- hibition by GABA in a temporal lobe epilepsy model. Science 1996;271: Gibbs JW, Shumate MD, Coulter DA. Differential epilepsyassociated alterations in postsynaptic GABAA receptor function in dentate granule cells and CAI neurons. J Neurophysiol 1997;77: Brooks-Kayal AR, Shumate MD, Jin H, Rikhter TY, Coulter DA. Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nut Med 1998;4: Bernard C, Esclapez M, Hirsch JC, Ben-Ari Y. Interneurones are not so dormant in temporal lobe epilepsy: a critical reappraisal of the dormant basket cell hypothesis. Epilepsy Res 1998;32: Turner D, Wheal H. Excitatory synaptic potentials in kainic aciddenervated rat CAI pyramidal neurons. J Neurosci 1991;11: Fricker D, Verheugen JA, Miles R. Cell-attached measurements of the firing threshold of rat hippocampal neurons. J Physiol 1999; 517: Verheugen JA, Fricker D, Miles R. Noninvasive measurements of the membrane potential and GABAergic action in hippocampal interneurons. J Neurosci 1999;19: Hirsch JC, Cossart R, Esclapez M, Ben-Ari Y, Bernard C. Reversal of the balance between excitation and inhibition in hippocampal CA1 interneurones in experimental epilepsy. Soc Neurosci Abstr 1999;29: Turner D. Waveform and amplitude characteristics of evoked responses to dendritic stimulation of CA1 guinea-pig pyramidal cells. J Physiol 1988;395: Andersen P, Storm J, Wheal HV. Thresholds of action potentials evoked by synapses on the dendrites of pyramidal cells in the rat hippocampus in vitro. J Physiol 1987;383: Turner DA. Conductance transients onto dendritic spines in a segmental cable model of hippocampal neurons. Biophys J 1984;46: Spruston N, Jaffe D, Williams S, Johnston D. Voltage- and spaceclamp errors associated with the measurement of electronically remote synaptic events. J Neurophysiol 1993;70: Nusser Z, Hajos N, Somogyi P, Mody I. Increased number of synaptic GABA(A) receptors underlies potentiation at hippocampal inhibitory synapses. Nature 1998;395: Mangan PS, Lothman EW. Profound disturbances of pre- and postsynaptic GABAB-receptor-mediated processes in region CAI in a chronic model of temporal lobe epilepsy. J Neurophysiol 1996;76: Otis TS, Staley KJ, Mody I. Perpetual inhibitory activity in mammalian brain slices generated by spontaneous GABA release. Bruin Res : Chen K, Baram TZ, Soltesz I. Febrile seizures in the developing brain result in persistent modification of neuronal excitability in limbic circuits. Nut Med 1999;5: Bernard C, Esclapez M, Agid F, Ben-Ari Y, Hirsch JC. Selective loss of GABAergic inhibition in the apical dendrites of CAI pyramidal neurons in temporal lobe epilepsy. Soc Neurosci Abstr 1997;23: Beau FL, Alger BE. Transient suppression of GABAA-receptormediated IPSPs after epileptiform burst discharges in CA1 pyramidal cells. J Neurophysiol 1998;79: Isokawa M. Modulation of GABAA receptor-mediated inhibition by postsynaptic calcium in epileptic hippocampal neurons. Bruin Res 1998;810: Epilepsia, Vol. 41, Suppl. 6, 2000