Regulation of GABA_A Receptor Gene Expression and Epilepsy

Epileptogenesis, is associated with changes in the expression of a multitude of genes, including those related to inhibitory neurotransmission, and alterations in many of these genes and their gene products may be critical contributors to hyperexcitability. The GABA_A receptor (GABAR) mediates most fast synaptic inhibition in brain, and changes in GABAR subunit expression and function appear to directly contribute to epileptogenesis. Results of our studies indicate that GABAR regulation after SE occurs in response to increased synthesis of brain-derived neurotrophic factor (BDNF) and activation of its receptors (TrkB and p75) that control a number of down-stream pathways, including Janus kinase (JAK)/Signal Transducer and Activators of Transcription (STAT), protein kinase C, and mitogen activated protein kinase (MAPK). Transcriptional sensors for pathway activation, such as cAMP response element binding protein (CREB), inducible cAMP response element repressor, and early growth response factor 3 (Egr3) regulate α1 and α4 subunit gene expression in parallel resulting in specific changes in GABAR populations that may contribute to hyperexcitability. In this chapter, we will discuss the results of our studies in the context of how they may provide novel therapeutic approaches for preventing or inhibiting development and progression of epilepsy after a precipitating insult.