Disruption of Trophic Inhibitory Signaling in Autism Spectrum Disorders

Project: Research project

Project Details


Autism spectrum disorders (ASDs) are a group of prevalent neurodevelopmental disorders with a strong genetic component that have complex and heterogeneous symptom presentation. Despite the molecular heterogeneity underlying ASDs there exist several shared and convergent alterations in synaptic function and development that have been linked to altered cognition in ASD models. Even diverse, unrelated syndromic and non-syndromic types of autism share multiple cellular and physiological abnormalities; this suggests that understanding the shared synaptic and circuit alterations in the cortex of mice will uncover potential targets for developing treatments for ASDs. As a result, the development of genetically modified mice that model monogenic human syndromic ASDs have provided a way to determine common pathophysiological mechanisms that can be generalized to a large number of ASDs. Preliminary studies in our laboratories have demonstrated that there is network hyperexcitability and a delay in the closure of the critical period of experience-dependent synaptic plasticity in the somatosensory cortex of Fmr1 ko mice, a model of syndromic ASD (fragile X syndrome). Furthermore we discovered that the normal switch from depolarizing to hyperpolarizing GABA responses is delayed in cortical neurons. We propose that alteration of the normal trophic effects of depolarizing GABA play a primary role in the altered synaptic, cellular, and network development. The objectives of this proposal are two-fold. The first objective is to determine whether convergent alterations in chloride homeostasis are present in multiple syndromic ASD mouse models (Fmr1 ko and Ube3a null mice), as well as in human neurons derived from iPS cells from patients with ASDs. The second objective is to determine whether the alteration in the development of depolarizing GABA is causal to the altered synaptic and network properties in the neocortex of ASD mouse models. This will be achieved by normalizing chloride homeostasis by blocking the juvenile chloride (Cl-) cotransporter in vivo and determining if we can rescue the synaptic and network alterations.
Effective start/end date9/30/149/29/16


  • U.S. Army Medical Research and Materiel Command (W81XWH-14-1-0433)


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