Abstracts

Recent anatomical and physiological studies have demonstrated that after pilocarpine-induced status epilepticus, there is reduction of parvalbumin and somatostatin interneurons and the frequency of spontaneous IPSCs in granule cells of the dentate gyrus preceding the development of spontaneous seizures (Kobayashi and Buckmaster, J. Neurosci. 23: 2440-2452, 2003). After ~ 100 evoked Class V kindled seizures, there is reduction of CCK and GAT-1 interneurons providing axo-somatic and axo-axonic inhibition to granule cells in the dentate gyrus, which is accompanied by reduced amplitude and duration of evoked IPSCs and the emergence of spontaneous seizures (Sayin et al., J. Neurosci. 23: 2759-2768, 2003). As these observations suggest that seizure-induced loss of specific interneuron subclasses in the dentate gyrus may contribute to emergence of spontaneous seizures, it was of interest to determine if spontaneous seizures are also associated with loss of specific interneurons and inhibition in CA3.
Paired pulse inhibition and GAT-1 and CCK interneuron populations in CA3 were assessed in kindled rats after a range of 3 ADs to [gt] 100 Class V seizures and were compared to age-matched controls. Paired pulse inhibition was measured in hippocampal slices by recording field potentials in the stratum pyramidale in response to stimulation of the granule cell layer of the dentate gyrus at interstimulus intervals of 15-300 msec. CCK and GAT-1 interneuron populations were examined by immunohistochemical and stereological methods in kindled rats that experienced 3, 60-80, or [gt]100 Class V seizures.
After 90-100 evoked Class V seizures, there was a loss of paired pulse inhibition at 15-25 msec interpulse intervals in CA3 (n = 20), which was not observed in age-matched controls (n = 58) or kindled rats that experienced 3ADs or 3-35 Class V seizures (n = 21, P[lt] 0.001, ANOVA). The loss of paired pulse inhibition in CA3 was consistent with loss of GABA[sub]A[/sub]inhibition and was temporally associated with emergence of spontaneous seizures and loss of inhibition in the dentate gyrus. In contrast to the loss of both CCK and GAT-1 interneurons in the dentate gyrus at this kindling stage, GAT-1 immunoreactivity was reduced in CA3, but no loss of CCK interneurons was detected by stereological counting methods (n = 4).
The emergence of spontaneous seizures is associated with loss of paired pulse inhibition in both dentate gyrus and CA3. In the dentate gyrus, the loss of inhibition may be caused by seizure-induced loss of CCK and GAT-1 interneurons providing axo-somatic and axo-axonic inhibition. In CA3, the lack of evidence for CCK interneuron loss indicates that seizures induce regionally specific interneuron loss in hippocampal circuitry, and that specific seizure-induced cellular alterations are likely to contribute to the loss of inhibition in different regions of hippocampal circuitry.
[Supported by: NINDS 25020, VA Resesarch]