Mechanisms of Kainic Acid- Induced Epileptiform Activity in the Rat

Abstract

Depression of GABA-mediated IPSPs has been proposed to be a crucial factor in the onset of epileptiform activity in most models of epilepsy. To test this idea, we studied epileptiform activity induced by bath application of the excitatory neurotoxin kainic acid (KA) in the rat hippocampal slice. Repetitive field potential firing, spontaneous or evoked, occurred during exposure to KA. Intracellular records from 52 CA1 pyramidal cells during changes from control saline to saline containing i PM KA indicated that KA depolarized cells an average of about 5 mV and caused a 15% decrease in input resistance. Action potentials and current-induced burst afterhyperpolarizations did not change significantly. In several cells the tonic effects of KA were preceded by a transient phase of sporadic, spontaneous depolarizations of 2 to 10 mV and 50 to 200 msec duration. These phasic depolarizations were blocked by hyperpolarization. The major effect of 1 PM KA was a depression of synaptic potentials. Initially, KA depressed fast GABA-mediated IPSPs and slow, non-GABA-mediated late hyperpolarizing potentials to 23% and 40% of control values, respectively. IPSP depression correlated closely with onset of burst potential firing in response to synaptic stimulation. Similar observations were made on six cells from the CA213 region, although these cells were affected by lower doses of KA. The mechanism of IPSP depression was studied by using KCl-filled electrodes to invert spontaneous IPSPs and make them readily visible. In nine CA1 cells the rate and amplitude of spontaneous IPSPs transiently increased but then decreased in conjunction with evoked IPSP depression. Possible KA effects on postsynaptic GABA responses were investigated by applying GABA locally to cells. KA did not significantly affect GABA responses. Prolonged exposure of CA1 cells to KA in doses of 1 PM or higher depressed intracellularly and extracellularly recorded EPSPs and all field potential activity. This depression was not apparently due to depolarization block in CAl, however. We conclude that KA induces epileptiform activity in hippocampus principally by a presynaptic block of IPSP pathways. Recent studies of epileptiform activity induced by bicuculline (Schwartzkroin and Prince, 1980), picrotoxin (Alger and Nicoll, 1980a), or penicillin (Wong and Prince, 1979; Dingledine and Gjerstad, 1980) in the in vitro hippocampal slice preparation have shown that reduction of pyramidal cell IPSPs is closely associated with the onset of repetitive cell firing and epileptiform extracellular field potential discharges. To test whether disinhibition is a necessary factor in generation of epi’ This work was supported by National Institutes of Health Grant NS17539 and a McKnight Foundation Scholar’s Award (B. E. A.) and by TIDA 5K07NS00697 (R. S. F.) * To whom reprint requests should be sent, at his current address: Department of Neurology, Meyer Building, Room 5109, Johns Hopkins Hospital, Baltimore MD 21205. leptiform discharges, we have examined the electrophysiology of kainic acid (KA)-induced discharges in the rat hippocampal slice. KA is a conformationally rigid analogue of glutamic acid (Kizer et al., 1978), a putative excitatory neurotransmitter in the hippocampus (Nadler et al., 1976). In moderate doses it induces behavioral and electroencephalographic seizures analogous to clinical complex partial seizures (Nadler, 1981), whereas in high doses it causes “toxic” changes in cells (McGeer et al., 1978). Excitatory effects of KA were first described for rat neocortical cells (Shinozaki and Konishi, 1970). Subsequently KA has been shown to excite motoneurons (Biscoe et al., 1976; Engberg et al., 1978), dorsal root fibers (Constanti and Nistri, 1976; Evans, 1980), Renshaw interneurons (Johnston et al., 1974), rat thalamic neurons (Hall et al., 1979),

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@inproceedings{SLICE2003MechanismsOK, title={Mechanisms of Kainic Acid- Induced Epileptiform Activity in the Rat}, author={HIPPOCAMPAL SLICE and Robert S. Fisher and Bradley E. Alger}, year={2003} }