LATERAL INHIBITION AND GRANULE CELL SYNCHRONY IN THE RAT HIPPOCAMPAL DENTATE GYRUS

Studies of patients with temporal lobe epilepsy and of experimental mo dels of this disorder suggest that the hippocampal dentate gyrus may b e a common site of seizure onset and propagation, However, the nature of the dentate ''network defect'' that could give rise to spontaneous, intermittent, and synchronous population discharges is poorly underst ood, We have hypothesized that large expanses of the dentate granule c ell layer have an underlying tendency to discharge synchronously in re sponse to afferent excitation, but do not do so normally because vulne rable dentate hilar neurons establish lateral inhibition in the granul e cell layer and thereby prevent focal discharges from spreading to su rrounding segments, To address this hypothesis, we (1) identified func tionally independent segments of the granule cell layer; (2) determine d whether discharges in one segment evoke lateral inhibition in surrou nding segments; and, (3) determined if disinhibition induces normally independent segments of the granule cell layer to discharge synchronou sly, Simultaneous extracellular recordings were made from two location s along the longitudinal or transverse axes of the granule cell layer using saline- and bicuculline-filled electrodes that were glued togeth er, Leakage of 10 mM bicuculline from the electrode tip produced no de tectable spontaneous activity, However, single perforant path stimuli evoked multiple population spikes at the bicuculline electrode and sim ultaneous normal responses at the nearby saline electrode. The multipl e spikes evoked at the bicuculline electrode did not propagate to, and were not detected by, the adjacent saline electrode, indicating funct ional separation between neighboring subgroups of granule cells, Paire d-pulse stimulation revealed that multiple discharges were not only re stricted to one segment of the granule cell layer, but strongly inhibi ted surrounding segments, This lateral inhibition in surrounding segme nts often lasted longer than 150 msec, Finally, we evaluated granule c ell activity at two normally independent sites within the granule cell layer both before and after disinhibition was induced by high frequen cy stimulus trains or bicuculline injection. following a 10 sec, 20 Hz perforant path stimulus train, 2 Hz stimulation evoked virtually iden tical synchronized epileptiform discharges from normally separated sit es. Similarly, intrahippocampal or intravenous bicuculline injection p roduced spontaneous synchronous epileptiform discharges throughout the granule cell layer, These results indicate that lateral or ''surround '' inhibition is an operant physiological mechanism in the normal dent ate gyrus and suggest that afferent stimuli to a disinhibited dentate network evoke highly synchronized discharges from large expanses of th e granule cell layer that are normally kept functionally separated by GABA-mediated inhibition.