Disruption of Trophic Inhibitory Signaling in Autism Sepctrum Disorders

We have examined alterations in inhibitory GABA signaling in mouse models of ASDs as well as in human iPS derived neurons. We had previously demonstrated that the maturation of the reversal potential for GABA EGABA is delayed in the Fragile X mouse model. In this project we proposed to determine whether this alteration in the maturation of EGABA was a convergent alterations in ASDs with multiple genetic origins, which would make it an important target pathway in ASDs. Also we proposed to determine whether inhibiting one of the chloride co-transporters that control EGABA could be used as a corrective strategy for the synaptic and circuit disruptions demonstrated in the Fragile X mouse model. We found 1 that EGABA development was not disrupted in the mouse model of Angelman Syndrome 2 EGABA development was delayed in human induced neurons derived from Fragile X patient fibroblasts 3 Inhibiting the Cl- co-transporters that regulate EGABA by administration of bumetanide to mice rescues synaptic and circuit dysfunction in Fragile X mice.