Status Epilepticus (SE) is a devastating and often lethal human disease in which continuous or rapidly repeating seizures occur. The primary mechanism underlying the induction of SE is compromised of synaptic inhibition mediated by y-aminobutyric acid (GABA), and accordingly the frontline treatments for this condition center on benzodiazepines, which exert their action by enhancing the activity of GABAA receptors at the primary sites of fast synaptic inhibition in the brain. Universal observations in both patients and animal models of SE are altered GABAA receptor functional expression and decreased efficacy of receptor functional modulation by benzodiazepines. To date the molecular mechanism underlying these losses in the strength of synaptic inhibition remains unknown. We will evaluate the role that compromised GABAA receptor phosphorylation plays in the loss of GABAA receptor cell surface number and the efficacy of synaptic inhibition during SE. In addition we will examine whether specifically blocking the endocytosis of GABAA receptors with dominant negative agents can be used to reverse the deficits in synaptic inhibition seen in SE. Our efforts will center on three complementary but distinct experimental goals:
Specific Aim 1. We will test the hypothesis that phosphorylation of GABAA receptors is modified in SE.
Specific Aim 2. We will test the hypothesis that GABAA receptor cell surface number and receptor endocytic trafficking are compromised in SE.
Specific Aim 3. We will test the hypothesis that selectively decreasing GABAA receptor endocytosis enhances inhibitory synaptic transmission inSE. By performing these studies we will provide new insights into the molecular mechanisms responsible for the decreased efficacy of synaptic inhibition that is evident during SE. These insights may also lead to the development of novel therapeutic strategies which specifically block GABAA receptor endocytosis to increase the strength of synaptic inhibition and thereby alleviate SE.
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