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PMID: 23141534 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses.

Cell ·Vol. 151 ·No. 4 ·2012-11-09 ·Pages 709-723

Clement JP, Aceti M, Creson TK, Ozkan ED, Shi Y, Reish NJ, Almonte AG, Miller BH, Wiltgen BJ, Miller CA, Xu X, Rumbaugh G

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.

MeSH Terms
Animals Cognition Disorders/genetics,metabolism Dendritic Spines/metabolism Disease Models, Animal Female Haploinsufficiency Hippocampus/embryology,metabolism Humans Male Memory Mice Mice, Inbred C57BL Mice, Knockout Nerve Net/metabolism Synapses/metabolism ras GTPase-Activating Proteins/genetics,metabolism
Chemicals
Syngap1 protein, mouse ras GTPase-Activating Proteins
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Clement James P
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
Aceti Massimiliano
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
Creson Thomas K
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
Ozkan Emin D
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
Shi Yulin
Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697, USA.
Reish Nicholas J
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Almonte Antoine G
Department of Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Miller Brooke H
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.
Wiltgen Brian J
Department of Psychology, University of Virginia, Charlottesville, VA 22904, USA.
Miller Courtney A
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, FL 33458, USA.
Xu Xiangmin
Department of Anatomy and Neurobiology, University of California, Irvine, CA 92697, USA.
Rumbaugh Gavin
Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA. Electronic address: [email protected].
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2012.08.045
Email
[email protected]
Published
2012-11-09
Pages
709-723
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3500766
Subset
IM
Grants
NINDS NIH HHS · R01 NS064079 · United States
NICHD NIH HHS · R03 HD060672 · United States
NIDA NIH HHS · R00 DA023700 · United States
NIMH NIH HHS · R01 MH096847 · United States
NIDA NIH HHS · DA023700-04S1 · United States
NICHD NIH HHS · R03HD060672 · United States
NINDS NIH HHS · R01NS064079 · United States
NIDA NIH HHS · K99 DA023700 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2012.08.045 PMC Full Text View journal details
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