Portmann, T, Yang, M, Mao, R, Panagiotakos, G, Ellegood, J, Dolen, G, Bader, PL, Grueter, BA, Goold, C, Fisher, E, Clifford, K, Rengarajan, P, Kalikhman, D, Loureiro, D, Saw, NL, Zhengqui, Z, Miller, MA, Lerch, JP, Henkelman, RM, Shamloo, M, Malenka, RC, Crawley, JN and Dolmetsch, RE (2014) Behavioral Abnormalities and Circuit Defects in the Basal Ganglia of a Mouse Model of 16p11.2 Deletion Syndrome. Cell reports.

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

Item Type:	Article
Additional Information:	NIBR author: Dolmetsch, RE institute: NIBR- address only contributor address: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA; School of Medicine, Stanford University, Stanford, CA 94305-5345, USALaboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USADepartment of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA; School of Medicine, Stanford University, Stanford, CA 94305-5345, USADepartment of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA; School of Medicine, Stanford University, Stanford, CA 94305-5345, USA; Neurosciences Program, Stanford University, Stanford, CA 94305-5345, USAMouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, ON M5T 3H7, CanadaDepartment of Neuroscience, Brain Science Institute, Johns Hopkins University, Baltimore, MD 21205, USASchool of Medicine, Stanford University, Stanford, CA 94305-5345, USA; Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305-5345, USASchool of Medicine, Stanford University, Stanford, CA 94305-5345, USA; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305-5345, USADepartment of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA; School of Medicine, Stanford University, Stanford, CA 94305-5345, USADepartment of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA; School of Medicine, Stanford University, Stanford, CA 94305-5345, USADepartment of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA; School of Medicine, Stanford University, Stanford, CA 94305-5345, USADepartment of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA; School of Medicine, Stanford University, Stanford, CA 94305-5345, USALaboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USALaboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USAStanford Behavioral and Functional Neuroscience Laboratory, Stanford, CA 94305-5345, USAStanford Behavioral and Functional Neuroscience Laboratory, Stanford, CA 94305-5345, USAStanford Behavioral and Functional Neuroscience Laboratory, Stanford, CA 94305-5345, USAMouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, ON M5T 3H7, Canada; Deparment of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, CanadaMouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, ON M5T 3H7, Canada; Deparment of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, CanadaSchool of Medicine, Stanford University, Stanford, CA 94305-5345, USA; Stanford Behavioral and Functional Neuroscience Laboratory, Stanford, CA 94305-5345, USA; Stanford Institute for Neuro-Innovation and Translational Neurosciences, Stanford, CA 94305-5345, USASchool of Medicine, Stanford University, Stanford, CA 94305-5345, USA; Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305-5345, USALaboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USADepartment of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA; Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA. Electronic address: ricardo.dolmetsch@novartis.com
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/22669