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Cell Rep. 2014 May 22;7(4):1077-1092. doi: 10.1016/j.celrep.2014.03.036. Epub 2014 May 1.

Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome.

Author information

1
Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA.
2
School of Medicine, Stanford University, Stanford, CA 94305-5345, USA.
3
Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USA.
4
Neurosciences Program, Stanford University, Stanford, CA 94305-5345, USA.
5
Mouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, ON M5T 3H7, Canada.
6
Department of Neuroscience, Brain Science Institute, Johns Hopkins University, Baltimore, MD 21205, USA.
7
Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305-5345, USA.
8
Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305-5345, USA.
9
Stanford Behavioral and Functional Neuroscience Laboratory, Stanford, CA 94305-5345, USA.
10
Deparment of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
11
Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford, CA 94305-5345, USA.
12
Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
#
Contributed equally

Abstract

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.

PMID:
24794428
PMCID:
PMC4251471
DOI:
10.1016/j.celrep.2014.03.036
[Indexed for MEDLINE]
Free PMC Article
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