Pathogenic SYNGAP1 Mutations Impair Cognitive Development by Disrupting Maturation of Dendritic Spine Synapses

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. [Display omitted] ► Pathogenic SYNGAP1 mutations promote early maturation of hippocampal spine synapses ► Mutations lead to neonatal hyperactivity of the hippocampal trisynaptic circuit ► Mutations have greatest impact during the first 3 weeks of development ► Reversal of mutations in adults does not improve behavior and cognition A monogenic mouse model connects premature development of hippocampal dendritic spine synapses to life-long disruptions in cognition and memory. These findings indicate that the pace of synapse maturation in early life is a critical determinant of normal intellectual development.