Despite the genetic heterogeneity underlying autism and neurodevelopmental syndromes with autism comorbidity, there is phenotypic convergence among these disorders, leading to the view that this may reflect a common pathological convergence in cortical circuits. A leading theory suggests that an increased ratio of excitatory to inhibitory (E/I) neurotransmission (i.e., E/I imbalance) within neocortical circuits contributes to the common phenotypic features of autism. To gain a genetic toehold for understanding E/I imbalance, we have focused on an autism disorder associated with changes in a single gene, UBE3A. Loss of UBE3A expression causes Angelman syndrome (AS), which is characterized by an absence of speech, cognitive disability, seizures, and a high comorbidity with autism. We recently demonstrated that inhibitory drive onto cortical pyramidal neurons is severely decreased in a mouse model of AS, resulting in an elevated E/I ratio. Our preliminary data led us to hypothesize that the E/I imbalance caused by loss of UBE3A protein reflects both presynaptic defects in inhibitory interneurons and postsynaptic defects in pyramidal neurons. We further hypothesize that UBE3A function is required to maintain cortical E/I balance, and therefore we predict that loss of UBE3A even in adults will increase seizure susceptibility and cognitive deficits associated with elevated E/I ratio. Furthermore, we hypothesize that reinstatement of Ube3a expression will restore cortical E/I balance and reverse some AS phenotypes. In this proposal we aim to (1) Elucidate the cellular basis of cortical E/I imbalance in AS;(2) Test the hypothesis that Ube3a expression is required throughout life to maintain cortical E/I balance and neurotypical behaviors;(3) Define treatment windows for AS phenotypes. Our research will help establish parameters for therapeutic interventions in AS and possibly other autism spectrum disorders.

Public Health Relevance

Angelman syndrome is a devastating neurological disorder characterized by intellectual disability, lack of speech, motor impairments, epilepsy, and high comorbidity with autism. Our study will reveal the cell types, synaptic defects, and ages that should be targeted to treat Angelman syndrome and perhaps other autism spectrum disorders of similar pathophysiology.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Developmental Brain Disorders Study Section (DBD)
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Mamounas, Laura
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
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Banerjee, Abhishek; Larsen, Rylan S; Philpot, Benjamin D et al. (2016) Roles of Presynaptic NMDA Receptors in Neurotransmission and Plasticity. Trends Neurosci 39:26-39
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