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; Mark Henkelman; Mehrdad Shamloo; Robert C Malenka; Jacqueline N Crawley; Ricardo E Dolmetsch

doi:10.1016/j.celrep.2014.03.036

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

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

Authors

Thomas Portmann^{1

2}, Mu Yang^#³, Rong Mao^#^{1

2}, Georgia Panagiotakos^#^{1

2

4}, Jacob Ellegood⁵, Gul Dolen⁶, Patrick L Bader^{2

7}, Brad A Grueter^{2

8}, Carleton Goold^{1

2}, Elaine Fisher^{1

2}, Katherine Clifford^{1

2}, Pavitra Rengarajan^{1

2}, David Kalikhman³, Darren Loureiro³, Nay L Saw⁹, Zhou Zhengqui⁹, Michael A Miller⁹, Jason P Lerch^{5

10}, Mark Henkelman^{5

10}, Mehrdad Shamloo^{2

9

11}, Robert C Malenka^{2

8}, Jacqueline N Crawley³, Ricardo E Dolmetsch^{1

12}

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autistic Disorder / genetics*
Basal Ganglia / abnormalities*
Basal Ganglia / pathology
Chromosome Deletion*
Chromosome Disorders / genetics*
Chromosomes, Human, Pair 16 / genetics
Disease Models, Animal*
Female
Humans
Intellectual Disability / genetics*
Male
Mental Disorders / genetics*
Mice
Mice, Inbred C57BL
Mice, Transgenic

Supplementary concepts

16p11.2 Deletion Syndrome

Abstract

Publication types

MeSH terms

Supplementary concepts

Grants and funding