REGIONAL HETEROGENEITY OF PATHOPHYSIOLOGICAL ALTERATIONS IN CA1 AND DENTATE GYRUS IN A CHRONIC MODEL OF TEMPORAL-LOBE EPILEPSY

1. Extracellular and intracellular recording techniques were employed in brain slice preparations to characterize responses of hippocampal t issue in the post-self sustaining Limbic status epilepticus (post-SSLS E) model of chronic temporal robe epilepsy (TLE) as compared with resp onses in slices from control animals. Experiments were performed great er than or equal to 1 mo, and up to 7 mo, after status epilepticus. Tw o regions of the hippocampal formation linked to different aspects of epileptogenesis, the CAI region acid the dentate gyrus (DG), were stud ied. In any given experiment, CA1 and DG were examined in different sl ices from the same animal. 2. Pyramidal cells in CAI were activated by means of electrodes positioned over fiber bundles that monosynaptical ly project to these cells, either those located in the stratum lacunos um/moleculare or those in the stratum radiatum. Granule cells were sim ilarly activated by electrodes positioned in the perforant path. Full input-output curves were determined by varying stimulus strength and c harting the amplitudes of population spikes (PSs). 3. Two indexes, sti mulus sensitivity and responsiveness, were quantified in control tissu e 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 t o evoke comparable responses in input-output curves, between control a nd post-SSLSE tissue. However, responsiveness, defined as the number o f extracellular PSs or intracellular action potentials (APs) elicited by a stimulus strength giving rise to maximal-amplitude PSs, proved a reliable method for identifying and categorizing epileptic responses. This index allowed for comparisons between anatomic 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 hyp erresponsiveness relative to control tissue. 4. Control tissue never e xhibited >2 PSs in either CAI or DG in response to stimuli that produc ed maximal-amplitude PSs. Therefore a criterion of greater than or equ al to 3 PSs was adopted to delineate tissue as hyperresponsive on the basis of extracellular responses. In CA1 about one half of the post-SS LSE slices displayed greater than or equal to 3 PSs with stimuli givin g maximal-amplitude PSs, meeting the criterion for hyperresponsiveness ; in DG about one fifth of the slices showed hyperresponsiveness. 5. C A1 and DG differed with respect to the spectrum of hyperresponsiveness they exhibited, this being more robust in CA1. The two regions studie d also showed heterogeneity with respect to maximal PS amplitudes. In post-SSLSE tissue, maximum CA1 PS amplitude, as evoked by either Schae ffer collateral or stratum lacunosum/moleculare stimulation, declined to one half to one third of control levels. Amplitudes of PSs evoked i n DG with perforant path stimulation in post-SSLSE tissue were not dif ferent from those evoked in control tissue. 6. Intracellular recording s were obtained to investigate the behavior of principal neurons (pyra midal cells in CA1 and granule cells in DG) in epileptic, post-SSLSE t issue relative to normal tissue. No alterations in resting membrane po tential, input resistance, or AP height were detected in either CA1 py ramidal cells or DG granule cells from epileptic tissue. The excitator y postsynaptic potential (EPSP)-inhibitory postsynaptic potential (IPS P) sequence of normal tissue in CA1 was replaced by a depolarization w ith 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 foun d. 7. Simultaneous extracellular and intracellular recordings revealed a close correlation between the number of PSs and APs in both control and epileptic tissue. This suggests that neurons of a region particip ate in a homogeneous fashion to shape the field response and that alth ough hyperresponsiveness 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 m odel mirrors observations made in human specimens obtained from patien ts with epilepsy at the time of surgery in that I) abnormalities are c hronic; 2) hyperresponsive, epileptiform paroxysms are readily evoked by synchronized, vigorous excitatory drive; and 3) spontaneous paroxys ms in vitro are rare. Our study revealed heterogeneities in the degree to which different hippocampal regions manifest the pathophysiology a ssociated with the post-SSLSE model of TLE. Region CA1 showed a greate r degrees of hyperresponsiveness and a larger deficit of inhibitory sy naptic transmission than did DG.