CHRONIC EPILEPSY WITH DAMAGE RESTRICTED TO THE HIPPOCAMPUS - POSSIBLEMECHANISMS

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 CA (4)-CA(3C), predominantly ipsilateral in CA(3), in CA(1) and in the gr anule 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 G ABA(B)-mediated long ISI-dependent inhibition. Yet no spontaneous seiz ures were observed at that time. In the next four weeks, we saw no evi dence of increasing excitatory drive such as would be expected from re current messy fiber sprouting. On the contrary, there was progressive return of inhibition. By four weeks post-lesion, the majority of anima ls 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 persis ted, but individual animals with complete recovery of frequency-depend ent inhibition showed spontaneous seizures, suggesting that loss of GA BA(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 m u A to the maximal population spike amplitude, a measure of granule ce ll excitability, was unchanged immediately after stimulation, but incr eased in the next few weeks in a manner identical to that seen in kind ling, suggesting the possibility that during the transient loss of inh ibition, spontaneous kindling had occurred. Intracellular recordings f rom granule cells in hippocampal slices prepared from these animals sh owed a significant loss of GABA(B)-mediated slow inhibitory postsynapt ic potentials (IPSPs). These data show that the sequellae of unilatera l status epilepticus with damage restricted to the hippocampus are suf ficient to cause chronic recurrent seizures. There is a possibility th at chronic epilepsy is not the direct result of the loss of inhibitory drive or of a sprouting-induced increase in excitatory drive, but rep resents plastic changes akin to spontaneous kindling, possibly facilit ated by loss of GABA(B)-mediated inhibition.