Chronic epilepsy with damage restricted to the hippocampus: possible mechanisms

Wasterlain, Claude G.; Shirasaka, Yukiyoshi; Mazarati, Andrey M.; Spigelman, Igor

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Volume 26, Issue 1 , Pages 255-265, December 1996

Chronic epilepsy with damage restricted to the hippocampus: possible mechanisms

Claude G. Wasterlain
- Corresponding author.
- Epilepsy Research Laboratory, VA Medical Center (127), Sepulveda, CA 91343-2099, USA
- Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90024, USA
- Brain Research Institute, UCLA School of Medicine, Los Angeles, CA 90024, USA
Yukiyoshi Shirasaka
- Epilepsy Research Laboratory, VA Medical Center (127), Sepulveda, CA 91343-2099, USA
- Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90024, USA
- Brain Research Institute, UCLA School of Medicine, Los Angeles, CA 90024, USA
Andrey M. Mazarati
- Epilepsy Research Laboratory, VA Medical Center (127), Sepulveda, CA 91343-2099, USA
- Department of Neurology, UCLA School of Medicine, Los Angeles, CA 90024, USA
Igor Spigelman
- Brain Research Institute, UCLA School of Medicine, Los Angeles, CA 90024, USA
- UCLA School of Dentistry, Los Angeles, CA 90024, USA

Received 29 November 1995; accepted 6 May 1996.

Abstract

We studied the time course and possible mechanisms of the development of chronic epilepsy following unilateral stimulation of the perforant path. After 24 h of perforant path stimulation by a modified Sloviter method, lesions were restricted to the hippocampus, except for 2 of 24 rats with minimal entorhinal neuronal injury in layer 3. Lesions were exclusively ipsilateral in the polymorph layer of the hilus and in Ca₄CA_3C, predominantly ipsilateral in CA₃, in CA₁ and in the granule cell layer. Feedforward and feedback inhibition were studied by paired pulse stimulation. In the week following inhibition, there was complete loss of GABA_A-mediated, short interstimulus interval (ISI)-dependent inhibition and frequency-dependent inhibition, and also of GABA_B-mediated long ISI-dependent inhibition. Yet no spontaneous seizures were observed at that time. In the next four weeks, we saw no evidence of increasing excitatory drive such as would be expected from recurrent mossy fiber sprouting. On the contrary, there was progressive return of inhibition. By four weeks post-lesion, the majority of animals had developed spontaneous recurrent seizures, and/or seizures on 2 Hz stimulation (never seen in controls), in spite of complete or near-complete recovery of short ISI-dependent, GABA_A-mediated inhibition. A small but significant loss of frequency-dependent inhibition persisted, but individual animals with complete recovery of frequency-dependent inhibition showed spontaneous seizures, suggesting that loss of GABA_A-mediated inhibition was not the direct cause of chronic epilepsy. GABA_B-mediated, long ISI-dependent inhibition continued to show a significant loss. The ratio of the population spike amplitude at 250 μA to the maximal population spike amplitude, a measure of granule cell excitability, was unchanged immediately after stimulation, but increased in the next few weeks in a manner identical to that seen in kindling, suggesting the possibility that during the transient loss of inhibition, spontaneous kindling had occurred. Intracellular recordings from granule cells in hippocampal slices prepared from these animals showed a significant loss of GABA_B-mediated slow inhibitory postsynaptic potentials (IPSPs). These data show that the sequellae of unilateral status epilepticus with damage restricted to the hippocampus are sufficient to cause chronic recurrent seizures. There is a possibility that chronic epilepsy is not the direct result of the loss of inhibitory drive or of a sprouting-induced increase in excitatory drive, but represents plastic changes akin to spontaneous kindling, possibly facilitated by loss of GABA_B-mediated inhibition.