This proposal is based on the hypothesis that the neuronal membrane depolarization mediated by intense activation of inhibitory GABAA receptors plays an important role in epileptogenesis, so that selectively modulating the ionic basis of this GABAergic depolarization represents a unique anticonvulsant strategy. The rationale for this hypothesis is based on the recent demonstration of a mechanism of activity-dependent GABAergic membrane depolarization: intense dendritic GABAA receptor activation results in differential collapse of the opposing transmembrane concentration gradients of HCO3 and Cl-, the anions that permeate the GABAA ionophore. The resulting shift of the GABAA reversal potential depolarizes the dendrites and enables excitatory NMDA receptor activation by diminishing the voltage- dependent Mg2+ block of the NMDA ionophore. Thus epileptogenic alterations in the balance between excitation and inhibition may occur due to activity-dependent shifts in anionic concentration gradients that change the function of GABAA receptors from inhibition to excitation. To test the hypothesis, the applicant will use whole-cell and extracellular recordings in the hippocampal slice preparation to 1) measure the transport rates of the anions that participate in the GABAergic depolarization 2) test how the modulation of those transport systems affects the activity-dependent GABAergic depolarization 3) test how the modulation of the ion transport systems affects epileptogenesis in acute in vitro seizure models. These experiments may provide alternative therapeutic strategies for seizures that are resistant to treatment with GABAergic anticonvulsants, including the barbiturates and benzodiazepines. Such strategies should prove particularly useful for neonatal seizures, since activity- dependent GABAergic neuronal excitation is especially prominent in the immature CNS, and the clinically available anticonvulsant acetazolamide has been shown in the applicant's preliminary studies to selectively block the GABAergic depolarization.
| Lillis, Kyle P; Wang, Zemin; Mail, Michelle et al. (2015) Evolution of Network Synchronization during Early Epileptogenesis Parallels Synaptic Circuit Alterations. J Neurosci 35:9920-34 |
| Staley, Kevin (2015) Molecular mechanisms of epilepsy. Nat Neurosci 18:367-72 |
