Dual Modulators of GABA-A and Alpha7 Nicotinic Receptors for Treating Autism
Annual rept. 5 Aug 2013 - 4 Aug 2014
CALIFORNIA UNIV IRVINE
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Autism spectrum disorder ASD is a polygenic signaling disorder that may result, in part, from an imbalance in excitatory and inhibitory neurotransmission at the network level which strongly suggests that inhibitory neurotransmission plays a key role perhaps as a result of deficits in g-aminobutyric acid-A receptor GABAAR mediated signaling. Therefore GABAARs may be a relevant therapeutic target for blocking or reversing the symptoms of ASD. Nicotinic cholinergic activity may supplementenhance GABA efficacy on cognitive function. Significant cognitive deficits are associated with ASD and extensive preclinical studiesclinical proof-of-concept trials support a crucial role for a7 nicotinic acetylcholine nACh receptors in mediating learning and memory processes. The purpose of our proposal is to test the hypothesis that the simultaneous and selective positive allosteric modulation of GABAA a7 nACh receptors will alleviate the core deficits and significant comorbidities of ASD. Our major findings are that selective positive allosteric modulation of 1-subunit containing GABAA receptor subtypes, by the test compound 2-261, impacts 1 aberrant behaviors reflected in sociability social interaction and 2 repetitive behavior stereotypy in the BTBR mouse model of ASD. These observations support the importance of the loss of inhibitory tone in these behavioral deficits and that the pharmacological enhancement this tone will help mitigate these deficits. Collectively, the observations made thus far support our working hypothesis and we will continue to test its validity in the coming year.