Abstracts

Rationale: The GABA A receptor mediates fast synaptic inhibition in brain and subunit composition influences its physiologic and pharmacologic properties. In adult animal models and human temporal lobe epilepsy (TLE), GABAR alpha1 subunit (GABRA1) mRNA levels decrease in dentate gyrus (DG) after status epilepticus (SE). Viral delivery of alpha1 into DG protects rats from development of spontaneous seizures following pilocarpine-induced SE, suggesting that alpha1 down-regulation may be a critical determinant of epileptogenesis. Further, we have recently found that both phosphorylated cAMP response element binding protein (pCREB) and its related family member inducible cAMP early repressor (ICER) increase after SE and are likely mediators of the alpha1 decreases. However, it remains unclear which cell signaling pathways are activated by SE to stimulate CREB/ICER repression of alpha1. We examined the role of brain derived neurotrophic factor (BDNF) in regulating CREB/ICER repression of alpha1 because BDNF has been shown to increase after SE and can also activate the CREB system. Methods: We examined effects of brain derived neurotrophic factor (BDNF) in regulating ICER and alpha1 in vitro in hippocampal neurons and in microdissected dentate gyrus after SE. Results: In vitro studies show that activation of brain derived neurotrophic factor (BDNF) can induce increases in ICER protein and decreases in alpha 1 in hippocampal neurons. Use of P6, a Jak/Stat pathway inhibitor, blocks these BDNF induced changes. We next examined whether the Jak/Stat pathway was also involved in the upstream mechanism of ICER regulation of GABRA1. In vivo examination of the Jak/Stat pathway reveals increases in pSTAT3 levels after SE from 1-48 hrs. Blockade of the Jak/Stat pathway in vivo with P6 injections into the hippocampus block the increases in both pSTAT3 and ICER levels. Conclusions: These findings indicate key regulation of GABRA1 by ICER may be mediated through BDNF stimulation of the Jak/Stat pathway and may enhance understanding of GABRA1 regulation and the mechanisms that result in the development of TLE after SE. [NIH F31 NS51943 to IVL, NIH NS051710 to ABK and SJR]