Behavioral Abnormalities and Circuit Defects in the Basal Ganglia of a Mouse Model of 16p11.2 Deletion Syndrome

Thomas Portmann; Mu Yang; Rong Mao; Georgia Panagiotakos; Jacob Ellegood; Gul Dolen; Patrick L. Bader; Brad A. Grueter; Carleton Goold; Elaine Fisher; Katherine Clifford; Pavitra Rengarajan; David Kalikhman; Darren Loureiro; Nay L. Saw; Zhou Zhengqui; Michael A. Miller; Jason P. Lerch; R. Mark Henkelman; Mehrdad Shamloo; Robert C. Malenka; Jacqueline N. Crawley; Ricardo E. Dolmetsch

doi:10.1016/j.celrep.2014.03.036

Cell Reports (May 2014)

Behavioral Abnormalities and Circuit Defects in the Basal Ganglia of a Mouse Model of 16p11.2 Deletion Syndrome

Thomas Portmann,
Mu Yang,
Rong Mao,
Georgia Panagiotakos,
Jacob Ellegood,
Gul Dolen,
Patrick L. Bader,
Brad A. Grueter,
Carleton Goold,
Elaine Fisher,
Katherine Clifford,
Pavitra Rengarajan,
David Kalikhman,
Darren Loureiro,
Nay L. Saw,
Zhou Zhengqui,
Michael A. Miller,
Jason P. Lerch,
R. Mark Henkelman,
Mehrdad Shamloo,
Robert C. Malenka,
Jacqueline N. Crawley,
Ricardo E. Dolmetsch

Affiliations

Thomas Portmann: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA
Mu Yang: Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USA
Rong Mao: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA
Georgia Panagiotakos: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA
Jacob Ellegood: Mouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, ON M5T 3H7, Canada
Gul Dolen: Department of Neuroscience, Brain Science Institute, Johns Hopkins University, Baltimore, MD 21205, USA
Patrick L. Bader: School of Medicine, Stanford University, Stanford, CA 94305-5345, USA
Brad A. Grueter: School of Medicine, Stanford University, Stanford, CA 94305-5345, USA
Carleton Goold: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA
Elaine Fisher: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA
Katherine Clifford: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA
Pavitra Rengarajan: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA
David Kalikhman: Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USA
Darren Loureiro: Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USA
Nay L. Saw: Stanford Behavioral and Functional Neuroscience Laboratory, Stanford, CA 94305-5345, USA
Zhou Zhengqui: Stanford Behavioral and Functional Neuroscience Laboratory, Stanford, CA 94305-5345, USA
Michael A. Miller: Stanford Behavioral and Functional Neuroscience Laboratory, Stanford, CA 94305-5345, USA
Jason P. Lerch: Mouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, ON M5T 3H7, Canada
R. Mark Henkelman: Mouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, ON M5T 3H7, Canada
Mehrdad Shamloo: School of Medicine, Stanford University, Stanford, CA 94305-5345, USA
Robert C. Malenka: School of Medicine, Stanford University, Stanford, CA 94305-5345, USA
Jacqueline N. Crawley: Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USA
Ricardo E. Dolmetsch: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA

DOI: https://doi.org/10.1016/j.celrep.2014.03.036
Journal volume & issue: Vol. 7, no. 4
pp. 1077 – 1092

Abstract

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A deletion on human chromosome 16p11.2 is associated with autism spectrum disorders. We deleted the syntenic region on mouse chromosome 7F3. MRI and high-throughput single-cell transcriptomics revealed anatomical and cellular abnormalities, particularly in cortex and striatum of juvenile mutant mice (16p11+/−). We found elevated numbers of striatal medium spiny neurons (MSNs) expressing the dopamine D2 receptor (Drd2+) and fewer dopamine-sensitive (Drd1+) neurons in deep layers of cortex. Electrophysiological recordings of Drd2+ MSN revealed synaptic defects, suggesting abnormal basal ganglia circuitry function in 16p11+/− mice. This is further supported by behavioral experiments showing hyperactivity, circling, and deficits in movement control. Strikingly, 16p11+/− mice showed a complete lack of habituation reminiscent of what is observed in some autistic individuals. Our findings unveil a fundamental role of genes affected by the 16p11.2 deletion in establishing the basal ganglia circuitry and provide insights in the pathophysiology of autism.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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