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 contributesto 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
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Lee, Hyeong-Min; Clark, Ellen P; Kuijer, M Bram et al. (2018) Characterization and structure-activity relationships of indenoisoquinoline-derived topoisomerase I inhibitors in unsilencing the dormant Ube3a gene associated with Angelman syndrome. Mol Autism 9:45
Sidorov, Michael S; Judson, Matthew C; Kim, Hyojin et al. (2018) Enhanced Operant Extinction and Prefrontal Excitability in a Mouse Model of Angelman Syndrome. J Neurosci 38:2671-2682
Wall, Mark J; Collins, Dawn R; Chery, Samantha L et al. (2018) The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility. Neuron 98:1124-1132.e7
McCoy, Eric S; Taylor-Blake, Bonnie; Aita, Megumi et al. (2017) Enhanced Nociception in Angelman Syndrome Model Mice. J Neurosci 37:10230-10239
Sidorov, Michael S; Deck, Gina M; Dolatshahi, Marjan et al. (2017) Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome: a parallel mouse and human analysis. J Neurodev Disord 9:17
Nagendran, Tharkika; Larsen, Rylan S; Bigler, Rebecca L et al. (2017) Distal axotomy enhances retrograde presynaptic excitability onto injured pyramidal neurons via trans-synaptic signaling. Nat Commun 8:625
Wallace, Michael L; van Woerden, Geeske M; Elgersma, Ype et al. (2017) Ube3a loss increases excitability and blunts orientation tuning in the visual cortex of Angelman syndrome model mice. J Neurophysiol 118:634-646
Burette, Alain C; Judson, Matthew C; Burette, Susan et al. (2017) Subcellular organization of UBE3A in neurons. J Comp Neurol 525:233-251
Judson, Matthew C; Burette, Alain C; Thaxton, Courtney L et al. (2017) Decreased Axon Caliber Underlies Loss of Fiber Tract Integrity, Disproportional Reductions in White Matter Volume, and Microcephaly in Angelman Syndrome Model Mice. J Neurosci 37:7347-7361
Judson, Matthew C; Wallace, Michael L; Sidorov, Michael S et al. (2016) GABAergic Neuron-Specific Loss of Ube3a Causes Angelman Syndrome-Like EEG Abnormalities and Enhances Seizure Susceptibility. Neuron 90:56-69

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