Interneuron-targeted disruption of SYNGAP1 alters sensory representations in neocortex and impairs sensory learning

Abstract

SYNGAP1 haploinsufficiency in humans results in severe neurodevelopmental disorders characterized by intellectual disability, autism, epilepsy, and sensory processing deficits. However, circuit mechanisms that underlie SYNGAP1-related neurodevelopmental disorders are poorly understood. A decrease of SynGAP in mice causes cognitive and behavioral deficits in part by disrupting the development of excitatory glutamatergic connections. Whether and to what extent SynGAP functions in inhibitory circuits remain unclear. We show that interneuron-specific SYNGAP1 heterozygous mice display learning deficits characterized by elevated behavioral responses in the absence of relevant sensory input and premature responses to a sensory input unrelated to reward acquisition. These behavioral deficits are associated with specific circuit abnormalities within primary somatosensory cortex, characterized by increased detrimental correlations and elevated responses to irrelevant sensory stimuli. Collectively, we show that a decrease of SynGAP in inhibitory interneurons disrupts sensory representation in the primary sensory cortex, which likely contributes to behavioral deficits.