Syngap1 promotes cognitive function through regulation of cortical sensorimotor dynamics.

Perception, a cognitive construct, emerges through sensorimotor integration (SMI). The genetic mechanisms that shape SMI required for perception are unknown. Here, we demonstrate in mice that expression of the autism/intellectual disability gene, Syngap1, in cortical excitatory neurons is required for the formation of somatomotor networks that promote SMI-mediated perception.

Promotes Cognitive Function through Regulation of Cortical Sensorimotor Dynamics.

Perception, a cognitive construct, emerges through sensorimotor integration (SMI). The genetic mechanisms that shape SMI required for perception are unknown. Here, we demonstrate in mice that expression of the autism/intellectual disability gene, , in cortical excitatory neurons is required for formation of somatomotor networks that promote SMI-mediated perception.

Endogenous alpha splice forms promote cognitive function and seizure protection.

Loss-of-function variants in cause a developmental encephalopathy defined by cognitive impairment, autistic features, and epilepsy. splicing leads to expression of distinct functional protein isoforms. Splicing imparts multiple cellular functions of SynGAP proteins through coding of distinct C-terminal motifs.

Re-expression of SynGAP protein in adulthood improves translatable measures of brain function and behavior.

It remains unclear to what extent neurodevelopmental disorder (NDD) risk genes retain functions into adulthood and how they may influence disease phenotypes. haploinsufficiency causes a severe NDD defined by autistic traits, cognitive impairment, and epilepsy. To determine if this gene retains therapeutically-relevant biological functions into adulthood, we performed a gene restoration technique in a mouse model for haploinsufficiency.

Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders.

SYNGAP1 loss-of-function variants are causally associated with intellectual disability, severe epilepsy, autism spectrum disorder and schizophrenia. While there are hundreds of genetic risk factors for neurodevelopmental disorders (NDDs), this gene is somewhat unique because of the frequency and penetrance of loss-of-function variants found in patients combined with the range of brain disorders associated with SYNGAP1 pathogenicity. These clinical findings indicate that SYNGAP1 regulates fundamental neurodevelopmental processes that are necessary for brain development.