The present program is based on 2 closely related discoveries that we have made recently: i) the diuretic, NKCC1 chloride importer antagonist, Bumetanide, that shifts the polarity of GABA from excitation to inhibition, decreases the severity of autism in children (Lemonnier et al., Transl Psych, 2012); ii) the oxytocin-mediated neuro-protective GABA excitatory-inhibitory shift that takes place during delivery is abolished in the valproate and fragile X rodent models of autism leading to persistent excitatory GABA, enhanced glutamatergic activity and gamma oscillations (Tyzio et al., Science, 2014). Pretreatment with bumetanide to the mother during the delivery period restores in offsprings physiological levels of chloride and attenuates the electrophysiological and behavioral autistic phenotypes (Tyzio et al., Science, 2014). Furthermore, blocking during the delivery period oxytocin signaling in naïve mothers produced autistic manifestations in off springs. These observations both confirm that intracellular chloride levels are elevated in autism and validate the potential use of Bumetanide as a treatment. In addition, our results, to the best of our knowledge, are the first ones that link an electrical event during delivery, a transmitter gated signal and a psychiatric disorder. Our current proposal is aimed at substantiating and generalizing our recent results suggesting important links between delivery, the polarity of GABA actions and autism. Our objectives are to determine if the deficient chloride regulation is a general feature of autism independently of the mutation by testing these alterations in other genetic models of autism and Tuberous Sclerosis. We shall also test if paravalbumin GABAergic interneurons (PV), that modulate the effects of oxytocin on brain networks, are altered early in autism, exciting their targets and affecting behaviorally relevant gamma oscillations. In addition, we will determine the mechanisms underlying the incidence of epilepsies in autism and the role of excitatory GABA. Finally, we shall examine if the administration of bumetanide outside the delivery period attenuates the pathogenesis of autism. This is important in order to better understand the priming role of the delivery process. The present program is highly innovative considering the complete lack of data on electrical activity of immature neurons in autism, the importance of developmental processes and our success in the therapeutic use of bumetanide to treat the disorder. This has considerable public health implications considering the links between complications during delivery, oxytocin and autism. The demonstration of common features between delivery, GABA signals, oxytocin, and various types of autism will impact heavily the research and treatment in autism and other developmental disorders. We do not anticipate an obstacle in performing the proposed project, as the techniques, preparations and animal models are available in the teams and their laboratories.