The inability to regulate the firing properties of neurons can lead to aberrant and excessive activity, oftentimes causing seizures. GABAA receptors are crucial for transmission of inhibitory signals which act as a brake on excessive activity to control and coordinate neuronal function. Deficits in the ?3 subunit of the GABAA receptor have been implicated in epilepsy in humans, and mice lacking ?3 suffer from seizures. However, the underlying mechanism for how loss of ?3 leads to susceptibility to seizures is still unknown. My preliminary data suggests that knockout of ?3 in hippocampal CA1 pyramidal cells affects transmission from a specific subset of inhibitory cells, but the precise identity of those cells remains to be determined. In addition, changes to the overall network activity of hippocampal cells resulting from deficits to these specific connections, and how these changes lead to epilepsy remains to be resolved.
I aim to use genetic, electrophysiological, imaging, and computational modeling methods to test the hypothesis that loss of the ?3 subunit in the CA1 region of the hippocampus results in specific circuit and network level disruptions underlying susceptibility to seizures. These studies will lay a foundation for the identification of potential avenues for therapeutic intervention while simultaneously elucidating basic mechanisms underlying seizure generation and epilepsy.
Altered inhibitory network signaling is an important mechanism underlying recurrent, spontaneous seizures. This proposal examines how loss of the ?3 subunit of the GABAA receptor in the CA1 region of the hippocampus leads to circuit and network level disruptions to inhibitory transmission, resulting in greater susceptibility to seizures. The resulting findings will identify new potential treatment targets and improve our understanding of neuronal circuits important for the inhibition of seizures.
