Abstracts

GABA[sub]A[/sub] receptors (GABAR) mediate most synaptic inhibition in the brain. Long-term GABAR alterations occur in hippocampal dentate granule neurons (DGN) of rats that develop temporal lobe epilepsy (TLE) after status epilepticus (SE) in adulthood, but whether these GABAR changes are critical determinants of epilepsy development remains unknown. We have found that changes in the most abundant GABAR [alpha]-subunit, [alpha]1, are markedly dependent on the age at which SE is induced and vary inversely with the likelihood of subsequent epilepsy development. Specifically, SE induced at postnatal day 10 increases [alpha]1 in DGN and does not cause epilepsy, while SE in adults decreases [alpha]1 and does cause epilepsy. These findings suggest that diminished [alpha]1 levels in DGN contribute to epileptogenesis and that elevated [alpha]1 levels could be protective. To investigate this question we utilized viral-mediated gene transfer to increase [alpha]1 levels in DGN following SE. Adult male Sprague-Dawley rats were stereotaxically-injected in dentate gyrus with 2 [mu]l of adeno-associated virus (AAV) containing an [alpha]1-transgene driven by a GABAR [alpha]4 subunit promoter that we have previously shown is specifically upregulated after SE. Two weeks following viral injections, rats receiving [alpha]1 gene transfer and sham injected controls were injected with pilocarpine to induce SE, then video monitored for 4 weeks following SE. Although SE was equivalent in both groups, 50% of the rats that had SE after [alpha]1 gene transfer [n=8] never had observed spontaneous seizures compared to 100% of the rats that had SE but were not treated with viral vector [n=6]. Further, AAV-injected animals that did develop spontaneous seizures showed a longer latency to seizure onset (10.25 days for AAV-injected vs. 4.5 days for controls). Increased [alpha]1 subunit protein expression in dentate of animals receiving the [alpha]1 gene transfer compared to sham-injected controls was confirmed by western blotting and immunohistochemistry. These data suggest that increasing GABAR [alpha]1 gene expression could have potential as an [quot]anti-epileptogenic[quot] therapy. (Supported by NIH NS42363-01 to ABK and SJR.)