Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism.

Abstract

Human neuroimaging studies suggest that aberrant neural connectivity underlies behavioural deficits in autism spectrum disorders (ASDs), but the molecular and neural circuit mechanisms underlying ASDs remain elusive. Here, we describe a complete knockout mouse model of the autism-associated Shank3 gene, with a deletion of exons 4-22 (Δe4-22). Both mGluR5-Homer scaffolds and mGluR5-mediated signalling are selectively altered in striatal neurons. These changes are associated with perturbed function at striatal synapses, abnormal brain morphology, aberrant structural connectivity and ASD-like behaviour. In vivo recording reveals that the cortico-striatal-thalamic circuit is tonically hyperactive in mutants, but becomes hypoactive during social behaviour. Manipulation of mGluR5 activity attenuates excessive grooming and instrumental learning differentially, and rescues impaired striatal synaptic plasticity in Δe4-22(-/-) mice. These findings show that deficiency of Shank3 can impair mGluR5-Homer scaffolding, resulting in cortico-striatal circuit abnormalities that underlie deficits in learning and ASD-like behaviours. These data suggest causal links between genetic, molecular, and circuit mechanisms underlying the pathophysiology of ASDs.

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Journal article

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Published Version (Please cite this version)

10.1038/ncomms11459

Publication Info

Wang, Xiaoming, Alexandra L Bey, Brittany M Katz, Alexandra Badea, Namsoo Kim, Lisa K David, Lara J Duffney, Sunil Kumar, et al. (2016). Altered mGluR5-Homer scaffolds and corticostriatal connectivity in a Shank3 complete knockout model of autism. Nat Commun, 7. p. 11459. 10.1038/ncomms11459 Retrieved from https://hdl.handle.net/10161/13004.

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Scholars@Duke

Bey

Alexandra L Bey

Assistant Professor of Psychiatry and Behavioral Sciences

Dr. Alexandra Bey holds both an M.D. and a PhD in Neurobiology. She serves as a Child Psychiatrist in the Duke Autism Clinic and is a valued member of the Duke University School of Medicine's Department of Psychiatry and Behavioral Sciences. Within the Division of Child and Family Mental Health and Community Psychiatry, Dr. Bey’s research and clinical career is dedicated to improving the lives of those with neurodevelopmental disorders. Her overarching research goal is to develop objective, relevant biomarkers to allow for more effective development and testing of novel therapies and to conduct translational research across preclinical models and in individuals with neurodevelopmental differences.

Badea

Alexandra Badea

Associate Professor in Radiology

I have a joint appointment in Radiology and Neurology and my research focuses on neurological conditions like Alzheimer’s disease. I work on imaging and analysis to provide a comprehensive characterization of the brain. MRI is particularly suitable for brain imaging, and diffusion tensor imaging is an important tool for studying brain microstructure, and the connectivity amongst gray matter regions.  

I am interested in image segmentation, morphometry and shape analysis, as well as in integrating information from MRI with genetics, and behavior. Our approaches  target: 1) phenotyping the neuroanatomy using imaging; 2) uncovering the link between structural and functional changes, the genetic bases, and environmental factors. I am interested in generating methods and tools for comprehensive phenotyping.

We use high-performance cluster computing to accelerate our image analysis. We use compressed sensing image reconstruction, and process large image arrays using deformable registration, perform segmentation based on multiple image contrasts including diffusion tensor imaging, as well as voxel, and graph analysis for connectomics.

At BIAC  my efforts focus on developing multivariate biomarkers and identifying vulnerable networks based on genetic risk for Alzheimer's disease.

My enthusiasm comes from the possibility to extend from single to integrative multivariate and network based analyses to obtain a comprehensive picture of normal development and aging, stages of disease, and the effects of treatments.  I am working on multivariate image analysis and predictive modeling approaches to help better understand early biomarkers for human disease indirectly through mouse models, as well as directly in human studies. 

I am dedicated to supporting an increase in female presence in STEM fields, and love working with students. The Bass Connections teams involve undergraduate students in research, providing them the opportunity to do independent research studies and get involved with the community. These students have for example takes classes such as:

BME 394: Projects in Biomedical Engineering (GE)
BME 493: Projects in Biomedical Engineering (GE)
ECE 899: Special Readings in Electrical Engineering
NEUROSCI 493: Research Independent Study 1


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