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

Cell | Nov 9, 2012

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.

Pubmed ID: 23141534 RIS Download

Mesh terms: Animals | Cognition Disorders | Dendritic Spines | Disease Models, Animal | Female | Haploinsufficiency | Hippocampus | Humans | Male | Memory | Mice | Mice, Inbred C57BL | Mice, Knockout | Nerve Net | Synapses | ras GTPase-Activating Proteins

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS064079
  • Agency: NICHD NIH HHS, Id: R03 HD060672
  • Agency: NIDA NIH HHS, Id: R00 DA023700
  • Agency: NIMH NIH HHS, Id: R01 MH096847
  • Agency: NIDA NIH HHS, Id: DA023700-04S1
  • Agency: NICHD NIH HHS, Id: R03HD060672
  • Agency: NINDS NIH HHS, Id: R01NS064079
  • Agency: NIDA NIH HHS, Id: K99 DA023700

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