The pathophysiology of epilepsy is intimately linked with imbalances of excitation and inhibition (E/I) in the brain. Although the loss of GABAergic inhibition is strongly implicated as a mechanism by which E/I imbalances arise in human epilepsy disorders, the molecular mechanisms that govern synaptic inhibition, and thereby maintain E/I balance, have been largely obscure. Recently, we discovered a novel inhibitory synaptic protein, Rogdi, whose gene is strongly linked to a human epilepsy disorder, Kohlschtter-Tnz syndrome. Preliminary data indicate that Rogdi may function either at the pre- or postsynapse where I hypothesize that it may regulate the synaptic vesicle cycle or protein trafficking. I propose to test this hypothesis and demonstrate Rogdi?s functional role at inhibitory synapses. Importantly, I will also determine if the loss of Rogdi is causal for seizures in mice. The successful completion of the proposed research will generate a new preclinical mouse model for studying Kohlschtter-Tnz syndrome and can be expected to generate an understanding of Rogdi?s molecular function and its contribution towards the etiology of a human epilepsy disorder.
Epilepsy, the condition of spontaneous recurrent seizures, is a devastating neurological disorder. Rare genetic mutations provide unique opportunities to understand the molecular mechanisms that drive susceptibility to seizures and epilepsy. This proposed work will study a human epilepsy candidate gene and can be expected to generate a deeper understanding of the molecular mechanisms underlying epilepsy.
