title: Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses.
abstract: Mutations that cause intellectual disability (ID) and autism spectrum disorder (ASD) are commonly found in genes that encode for synaptic proteins. However, it remains unclear how mutations that disrupt synapse function impact intellectual ability. In the SYNGAP1 mouse model of ID/ASD, we found that dendritic spine synapses develop prematurely during the early postnatal period. Premature spine maturation dramatically enhanced excitability in the developing hippocampus, which corresponded with the emergence of behavioral abnormalities. Inducing SYNGAP1 mutations after critical developmental windows closed had minimal impact on spine synapse function, whereas repairing these pathogenic mutations in adulthood did not improve behavior and cognition. These data demonstrate that SynGAP protein acts as a critical developmental repressor of neural excitability that promotes the development of life-long cognitive abilities. We propose that the pace of dendritic spine synapse maturation in early life is a critical determinant of normal intellectual development.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Clement
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Aceti
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Creson
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Emin D
authors.initials: ED
authors.lastname: Ozkan
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697, USA.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Reish
authors.affiliation: Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Antoine G
authors.initials: AG
authors.lastname: Almonte
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Brooke H
authors.initials: BH
authors.lastname: Miller
authors.affiliation: Department of Psychology, University of Virginia, Charlottesville, VA 22904, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Wiltgen
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697, USA.
authors.forename: Xiangmin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: grumbaug@scripps.edu.
authors.forename: Gavin
authors.initials: G
authors.lastname: Rumbaugh
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D057895:Haploinsufficiency; D006624:Hippocampus / Q000196:embryology / Q000378:metabolism; D006801:Humans; D008297:Male; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009415:Nerve Net / Q000378:metabolism; D013569:Synapses / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: C484512:Syngap1 protein, mouse; D020703:ras GTPase-Activating Proteins