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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS085093-01
Application #
8612194
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Mamounas, Laura
Project Start
2014-02-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
$321,269
Indirect Cost
$108,769
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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
Kim, Hyojin; Kunz, Portia A; Mooney, Richard et al. (2016) Maternal Loss of Ube3a Impairs Experience-Driven Dendritic Spine Maintenance in the Developing Visual Cortex. J Neurosci 36:4888-94
Jones, Kelly A; Han, Ji Eun; DeBruyne, Jason P et al. (2016) Persistent neuronal Ube3a expression in the suprachiasmatic nucleus of Angelman syndrome model mice. Sci Rep 6:28238
Xing, Lei; Larsen, Rylan S; Bjorklund, George Reed et al. (2016) Layer specific and general requirements for ERK/MAPK signaling in the developing neocortex. Elife 5:
Berrios, Janet; Stamatakis, Alice M; Kantak, Pranish A et al. (2016) Loss of UBE3A from TH-expressing neurons suppresses GABA co-release and enhances VTA-NAc optical self-stimulation. Nat Commun 7:10702
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
Katz, David M; Bird, Adrian; Coenraads, Monica et al. (2016) Rett Syndrome: Crossing the Threshold to Clinical Translation. Trends Neurosci 39:100-13
Niedringhaus, Mark; Dumitru, Raluca; Mabb, Angela M et al. (2015) Transferable neuronal mini-cultures to accelerate screening in primary and induced pluripotent stem cell-derived neurons. Sci Rep 5:8353
Bruinsma, Caroline F; Schonewille, Martijn; Gao, Zhenyu et al. (2015) Dissociation of locomotor and cerebellar deficits in a murine Angelman syndrome model. J Clin Invest 125:4305-15
Ehlen, J Christopher; Jones, Kelly A; Pinckney, Lennisha et al. (2015) Maternal Ube3a Loss Disrupts Sleep Homeostasis But Leaves Circadian Rhythmicity Largely Intact. J Neurosci 35:13587-98

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