REGIONAL HETEROGENEITY OF PATHOPHYSIOLOGICAL ALTERATIONS IN CA1 AND DENTATE GYRUS IN A CHRONIC MODEL OF TEMPORAL LOBE EPILEPSY. Rempe, David E., Patrick S. Mangan, and Eric W. Lothman. Department of Neurology and Neuroscience Program, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, U.S.A..
APStracts 2:0116N, 1995.
SUMMARY AND CONCLUSIONS
1) Extracellular and intracellular recording techniques were employed in brain slice preparations to characterize responses of hippocampal tissue in the post-self sustaining limbic status epilepticus (post-SSLSE) model of chronic temporal lobe epilepsy (TLE), as compared to responses in slices from control animals. Experiments were performed at least one month, and up to seven months, after status epilepticus. Two regions of the hippocampal formation linked to different aspects of epileptogenesis, the CA1 region and the dentate gyrus (DG), were studied. In any given experiment, CA1 and DG were examined in different slices from the same animal. 2) Pyramidal cells in CA1 were activated by means of electrodes positioned over fiber bundles that monosynaptically project to these cells, either those located in the stratum lacunosum/moleculare or those in the stratum radiatum. Granule cells were similarly activated by electrodes positioned in the perforant path. Full input-output curves were determined by varying stimulus strength and charting the amplitudes of population spikes (PS). 3) Two indices, stimulus sensitivity and responsiveness, were quantified in control tissue and in post-SSLSE tissue by means of input-output curves to provide comparisons between normal and epileptic tissue. There were no changes in stimulus sensitivity, defined as the stimulus intensity required to evoke comparable responses in input/output curves, between control and post-SSLSE tissue. However, responsiveness, defined as the number of extracellular PS or intracellular action potentials (AP) elicited by a stimulus strength giving rise to maximal amplitude PS, proved a reliable method for identifying and categorizing epileptic responses. This index allowed for comparisons between anatomical regions within an experiment as well as among experiments for the same region. Both CA1 pyramidal cells and DG granule cells from post-SSLSE tissue showed hyper- responsiveness relative to control tissue. 4) Control tissue never exhibited more than 2 PS in either CA1 or DG in response to stimuli that produced maximal amplitude PS. Therefore, a criterion of ¯> 3 PS was adopted to delineate tissue as hyper-responsive based on extracellular responses. In CA1 about one-half of the post-SSLSE slices displayed ¯> 3 PS with stimuli giving maximal amplitude PS, meeting the criterion for hyper-responsiveness; in DG about one-fifth of the slices showed hyper-responsiveness. 5) CA1 and DG differed with respect to the spectrum of hyper-responsiveness they exhibited, being more robust in CA1. The two regions studied also showed heterogeneity with respect to maximal PS amplitudes. In post-SSLSE tissue, maximum CA1 PS amplitude, as evoked by either Schaeffer collateral or stratum lacunosum/moleculare stimulation, declined to one-half to one-third of control levels. Amplitudes of PS evoked in DG with perforant path stimulation in post- SSLSE tissue were not different from those evoked in control tissue. 6) Intracellular recordings were obtained to investigate the behavior of principal neurons (pyramidal cells in CA1 and granule cells in DG) in epileptic, post-SSLSE tissue relative to normal tissue. No alterations in resting membrane potential, input resistance, or AP height were detected in either CA1 pyramidal cells or DG granule cells from epileptic tissue. The excitatory postsynaptic potential-inhibitory postsynaptic potential (EPSP- IPSP) sequence of normal tissue in CA1 was replaced by a depolarization with little or no IPSP in post-SSLSE tissue. In DG in post-SSLSE tissue an EPSP- IPSP sequence like that encountered in normal tissue was found. 7) Simultaneous extracellular and intracellular recordings revealed a close correlation between the number of PS and AP in both control and epileptic tissue. This suggests that neurons of a region participate in a homogeneous fashion to shape the field response and that while hyper-responsiveness varied across preparations it was uniform in a given preparation. 8) In conclusion, the post-SSLSE model provides a useful paradigm with which to study the pathophysiology of TLE. The model mirrors observations made in human specimens obtained from patients with epilepsy at the time of surgery in that: 1) abnormalities are chronic; 2) hyper-responsive, epileptiform paroxysms are readily evoked by synchronized, vigorous excitatory drive; and 3) spontaneous paroxysms in vitro are rare. Our study revealed heterogeneities in the degree to which different hippocampal regions manifest the pathophysiology associated with the post-SSLSE model of TLE. Region CA1 showed a greater degrees of hyper-responsiveness and a larger deficit of inhibitory synaptic transmission than did the dentate gyrus. 

Received 8 August 1994; accepted in final form 17 March 1995.
APS Manuscript Number J492-4.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on  1 May 1995.