A serious consequence of status epilepticus (SE) is memory impairment. Yet, remarkably little is known about the pathophysiological mechanisms responsible for this cognitive deficit. Exposing rats to status epilepticus during early adolescence causes impairment of spatial memory in the water maze and, in parallel, marked abnormalities in both the positional firing patterns of place cells and the stability of such patterns. These findings corroborate recent work demonstrating strong relationships between the ongoing activity of place cells and the ability of rats to perform adequately in spatial tasks. Thus, place cells may serve as a cell-level indicator of spatial memory, a very high level cognitive function of the rat hippocampus. A major goal of the studies proposed in this grant application is to rigorously test the idea that place cell abnormalities are markers of spatial memory impairment seen after induction of experimental epilepsy in rats.
Our first aim i s to determine the timing of place cell abnormalities following SE in adult rats and to compare this time course with the timing of changes in spatial memory and cerebral excitability. In this aim we will compare the time course of seizure-induced changes in hippocampal place cell function (firing rates, precision, and stability) with changes in cognitive function and hippocampal excitability. A critical question asked following SE is whether recurrent seizures or interictal epileptiform discharges (spikes and sharp waves) further harm cognitive function. Place cell studies provide us with the opportunity to examine the effects of seizures and spikes on cognitive function at the single cell level. Using mechanistically-oriented hypotheses we will determine whether spontaneous recurrent seizures and interictal epileptiform activity following SE alters place cell function. A key step in understanding the mechanisms of seizure-induced cognitive deficits is to determine whether place cell and visual-spatial memory impairment extend to other seizure insults.
Our third aim i s to assess the effects of serial seizures, which result in impaired water maze performance but have a distinctly different pathological pattern than SE, on place cell function. Taken together these studies will provide insight into the mechanisms of seizure-induced cognitive dysfunction which will be critical as we attempt to develop novel therapeutic interventions.
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