title: Behavioral abnormalities and circuit defects in the basal ganglia of a mouse model of 16p11.2 deletion syndrome.
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.
authors.affiliation: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA.|School of Medicine, Stanford University, Stanford, CA 94305-5345, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Portmann
authors.affiliation: Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USA.
authors.forename: Mu
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA.|School of Medicine, Stanford University, Stanford, CA 94305-5345, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Mao
authors.affiliation: Department 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, USA.
authors.forename: Georgia
authors.initials: G
authors.lastname: Panagiotakos
authors.affiliation: Mouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, ON M5T 3H7, Canada.
authors.forename: Jacob
authors.initials: J
authors.lastname: Ellegood
authors.affiliation: Department of Neuroscience, Brain Science Institute, Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Gul
authors.initials: G
authors.lastname: Dolen
authors.affiliation: School of Medicine, Stanford University, Stanford, CA 94305-5345, USA.|Department of Molecular and Cellular Physiology, Stanford University, Stanford, CA 94305-5345, USA.
authors.forename: Patrick L
authors.initials: PL
authors.lastname: Bader
authors.affiliation: School of Medicine, Stanford University, Stanford, CA 94305-5345, USA.|Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305-5345, USA.
authors.forename: Brad A
authors.initials: BA
authors.lastname: Grueter
authors.affiliation: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA.|School of Medicine, Stanford University, Stanford, CA 94305-5345, USA.
authors.forename: Carleton
authors.initials: C
authors.lastname: Goold
authors.affiliation: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA.|School of Medicine, Stanford University, Stanford, CA 94305-5345, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Fisher
authors.affiliation: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA.|School of Medicine, Stanford University, Stanford, CA 94305-5345, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Clifford
authors.affiliation: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA.|School of Medicine, Stanford University, Stanford, CA 94305-5345, USA.
authors.forename: Pavitra
authors.initials: P
authors.lastname: Rengarajan
authors.affiliation: Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USA.
authors.forename: David
authors.initials: D
authors.lastname: Kalikhman
authors.affiliation: Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USA.
authors.forename: Darren
authors.initials: D
authors.lastname: Loureiro
authors.affiliation: Stanford Behavioral and Functional Neuroscience Laboratory, Stanford, CA 94305-5345, USA.
authors.forename: Nay L
authors.initials: NL
authors.lastname: Saw
authors.affiliation: Stanford Behavioral and Functional Neuroscience Laboratory, Stanford, CA 94305-5345, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhengqui
authors.affiliation: Stanford Behavioral and Functional Neuroscience Laboratory, Stanford, CA 94305-5345, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Miller
authors.affiliation: Mouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, ON M5T 3H7, Canada.|Deparment of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Lerch
authors.affiliation: Mouse Imaging Centre (MICe), Hospital for Sick Children, Toronto, ON M5T 3H7, Canada.|Deparment of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
authors.forename: Mark
authors.initials: M
authors.lastname: Henkelman
authors.affiliation: School 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, USA.
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Shamloo
authors.affiliation: School of Medicine, Stanford University, Stanford, CA 94305-5345, USA.|Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305-5345, USA.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
authors.affiliation: Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892-9663, USA.
authors.forename: Jacqueline N
authors.initials: JN
authors.lastname: Crawley
authors.affiliation: Department of Neurobiology, Stanford University, Stanford, CA 94305-5345, USA.|Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Dolmetsch
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics*; D001479:Basal Ganglia / Q000002:abnormalities* / Q000473:pathology; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D001523:Mental Disorders / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic