Abstracts

Rationale: Stroke is the dominant cause of epilepsy in the elderly. Pathophysiological events associated with poststroke epileptogenesis include loss of cortical inhibitory GABAergic interneurons, which results in decreased GABAergic inhibition of cortical pyramidal neurons. Recent results from our lab using the technique of cortical photothrombosis indicated that seizures occurred more frequently and severely in aged rats and demonstrated limbic characteristics. In order to study the relationship of aging, cortical infarction, and limbic epileptogenesis, we characterized GABAA receptor (GABAAR) -mediated synaptic transmission in dentate granule cells (DGCs) one week following photothrombosis in 4 and 20 month old male Fischer 344 rats.Methods: Voltage-clamp (sIPSCs and mIPSCs) and current-clamp (resting membrane potential (RMP) and action potentials (APs)) were recorded from DGCs (n=95) in dorsal hippocampus from 4 mo control (n=4), 4 mo lesioned (n=4), 20 mo control (n=4), and 20 mo lesioned (n=4) animals with visualized patch-clamp. Lesioned animals were recorded ipsilateral to the cortical lesion. All group comparisons of electrophysiological data were assessed using unpaired t-tests, p<0.05.Results: Comparing 4 and 20 mo control groups, there was no difference in RMP but stimulus threshold for APs was significantly lower in the 4 mo group; there was no significant difference in AP amplitude, half-width, 10-90% rise time, and decay time constants. The mean amplitude of sIPSCs was significantly decreased in the 20 mo group with no change in frequency. Mean and median amplitude of mIPSCs was significantly reduced in the 20 mo group with no change in frequency. 10-90% rise time was significantly increased in 20 mo old controls with no change in decay time constants. Comparing 4 and 20 mo lesioned groups, RMP was more depolarized in the 20 mo group. No significant difference in stimulus threshold or threshold membrane potential of single APs was found; however, there were larger half-widths of single APs in the 20 mo group. There was no significant difference in the amplitude of single APs, but the 10-90% rise time of single APs in 20 mo group was increased; the decay time of single APs in the 20 mo group was increased. For sIPSCs, there was a reduction in the mean amplitude and frequency of the 20 mo group. For mIPSCs, median amplitude and frequency were reduced in the 20 mo group. 10-90% rise time was increased and the decay time was longer in the 20 mo group.Conclusions: These findings indicate that cortical infarction is followed by altered intrinsic membrane properties in DGCs and GABAAR functioning, key elements of the limbic system; these changes were exacerbated in aged animals. These plastic changes likely contribute to the increased excitatory tone of the dentate gyrus following permanent sensorimotor cortical ischemic infarction and may predispose it to the mechanisms of limbic epileptogenesis. Supported by NINDS R01NS46015 to KMK.