LOSS OF SYNAPTIC INHIBITION DURING REPETITIVE STIMULATION IN GENETICALLY EPILEPSY-PRONE RATS (GEPR)

Genetically epilepsy-prone rats (GEPR) are an animal model of generali zed motor seizures. The underlying causes of the predisposition to sei zures in GEPR have not been fully determined. The brainstem auditory s ystem is critical for audiogenic seizures in GEPR, and neurophysiologi cal abnormalities have been observed in these areas, but recent eviden ce suggests that non-auditory brain areas may also be abnormal. This m ay account for the lowered threshold in GEPR for various non-audiogeni c seizures. Because the normal responses of the hippocampal Schaffer c ollateral/CA1 synapse are relatively well understood, we studied singl e and repetitive synaptic responses in hippocampal slices of GEPR in v itro. Our hypothesis was that altered excitatory or inhibitory synapti c transmission may contribute to GEPR non-audiogenic seizure predispos ition. We recorded extracellular EPSPs, population spikes, and afferen t volleys in hippocampal area CA1, and compared GEPR responses to thos e of Sprague-Dawley (SD) rats, the strain from which GEPR were derived . GEPR responses to single synaptic stimuli were not significantly dif ferent from SD. The second of a pair of closely spaced EPSPs or popula tion spikes was larger in both GEPR and SD (paired pulse facilitation) , but the magnitude of population spike facilitation was significantly increased in GEPR. Short trains of four stimuli caused inhibition of population spike firing in SD, an effect that was much reduced in GEPR . When SD slices were treated with bicuculline, a GABA(A) receptor ant agonist, enhanced paired pulse facilitation and loss of inhibition dur ing trains of stimuli were seen, similar to the patterns seen in GEPR. Previous studies in another brain area of GEPR, inferior colliculus, have shown loss of neuronal inhibition, and pharmacologic studies were consistent with reduced GABA-mediated inhibition. The present study s uggests that abnormally reduced neuronal inhibition is also present in GEPR forebrain, and causes an exaggerated tendency to fire action pot entials, which may be a significant factor in GEPR seizure predisposit ion.