Cell Reports
Volume 7, Issue 4, 22 May 2014, Pages 1077-1092
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Article
Behavioral Abnormalities and Circuit Defects in the Basal Ganglia of a Mouse Model of 16p11.2 Deletion Syndrome

https://doi.org/10.1016/j.celrep.2014.03.036Get rights and content
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Highlights

  • The mouse model of human 16p11.2 deletion syndrome has defects in basal ganglia circuitry

  • Single-cell gene expression profiling reveals defects in dopamine-sensitive cell types

  • Mice exhibit synaptic defects and elevated numbers of medium spiny neurons

  • Behavioral defects include hyperactivity and cognitive deficits in the autism model

Summary

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.

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This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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These authors contributed equally to this work

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Present address: MIND Institute and Department of Psychiatry and Behavioral Sciences, UC Davis School of Medicine, Sacramento, CA 95817, USA