title: Adult restoration of Shank3 expression rescues selective autistic-like phenotypes.
abstract: Because autism spectrum disorders are neurodevelopmental disorders and patients typically display symptoms before the age of three, one of the key questions in autism research is whether the pathology is reversible in adults. Here we investigate the developmental requirement of Shank3 in mice, a prominent monogenic autism gene that is estimated to contribute to approximately 1% of all autism spectrum disorder cases. SHANK3 is a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of postsynaptic density macromolecular signalling complex. Disruptions of the Shank3 gene in mouse models have resulted in synaptic defects and autistic-like behaviours including anxiety, social interaction deficits, and repetitive behaviour. We generated a novel Shank3 conditional knock-in mouse model, and show that re-expression of the Shank3 gene in adult mice led to improvements in synaptic protein composition, spine density and neural function in the striatum. We also provide behavioural evidence that certain behavioural abnormalities including social interaction deficit and repetitive grooming behaviour could be rescued, while anxiety and motor coordination deficit could not be recovered in adulthood. Together, these results reveal the profound effect of post-developmental activation of Shank3 expression on neural function, and demonstrate a certain degree of continued plasticity in the adult diseased brain.
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Mei
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|PhD Programme in Experimental Biology and Biomedicine (PDBEB), Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Masaschusetts 02142, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Monteiro
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Jin-Ah
authors.initials: JA
authors.lastname: Kim
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Key Laboratory of Brain Functional Genomics (Ministry of Education &Science and Technology Commission of Shanghai Municipality), Institute of Cognitive Neuroscience, School of Psychology and Cognitve Science, East China Normal University, Shanghai 200062, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Gao
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Masaschusetts 02142, USA.
authors.forename: Zhanyan
authors.initials: Z
authors.lastname: Fu
authors.affiliation: McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.|Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Masaschusetts 02142, USA.
authors.forename: Guoping
authors.initials: G
authors.lastname: Feng
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics; D000818:Animals; D001007:Anxiety / Q000235:genetics; D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D049229:Dendritic Spines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D055879:Gene Knock-In Techniques; D006120:Grooming; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins; D019957:Motor Skills Disorders / Q000235:genetics / Q000503:physiopathology; D017072:Neostriatum / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000235:genetics; D010641:Phenotype; D057907:Post-Synaptic Density / Q000737:chemistry / Q000378:metabolism; D011597:Psychomotor Performance; D012919:Social Behavior
chemical_list: D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C492356:Shank3 protein, mouse