Interneuron-Targeted Disruption ofSYNGAP1Alters Sensory Representations in the Neocortex and Impairs Sensory Learning

Abstract

SYNGAP1haploinsufficiency in humans leads to severe neurodevelopmental disorders characterized by intellectual disability, autism, epilepsy, and sensory processing deficits. However, the circuit mechanisms underlying these disorders are not well understood. In mice, a decrease of SynGAP levels results in cognitive deficits by interfering with the development of excitatory glutamatergic connections. Recent evidence suggests that SynGAP also plays a crucial role in the development and function of GABAergic inhibitory interneurons. Nevertheless, it remains uncertain whether and to what extent the expression ofSYNGAP1in inhibitory interneurons contributes to cortical circuit function and related behaviors. The activity of cortical neurons has not been measured simultaneously with behavior. To address these gaps, we recorded from layer 2/3 neurons in the primary whisker somatosensory cortex (wS1) of mice while they learned to perform a whisker tactile detection task. Our results demonstrate that mice with interneuron-specificSYNGAP1haploinsufficiency exhibit learning deficits characterized by heightened behavioral responses in the absence of relevant sensory input and premature responses to unrelated sensory stimuli not associated with reward acquisition. These behavioral deficits are accompanied by specific circuit abnormalities within wS1. Interneuron-specificSYNGAP1haploinsufficiency increases detrimental neuronal correlations directly related to task performance and enhances responses to irrelevant sensory stimuli unrelated to the reward acquisition. In summary, our findings indicate that a reduction of SynGAP in inhibitory interneurons impairs sensory representation in the primary sensory cortex by disrupting neuronal correlations, which likely contributes to the observed cognitive deficits in mice with pan-neuronalSYNGAP1haploinsufficiency.SIGNIFICANCE STATEMENTSYNGAP1haploinsufficiency leads to severe neurodevelopmental disorders. The exact nature of neural circuit dysfunction caused bySYNGAP1haploinsufficiency remains poorly understood. SynGAP plays a critical role in the function of GABAergic inhibitory interneurons as well as glutamatergic pyramidal neurons in the neocortex. Whether and how decreasingSYNGAP1level in inhibitory interneurons disrupts a behaviorally relevant circuit remains unclear. We measure neural activity and behavior in mice learning a perceptual task. Mice with interneuron-targeted disruption ofSYNGAP1display increased detrimental neuronal correlations and elevated responses to irrelevant sensory inputs, which are related to impaired task performance. These results show that cortical interneuron dysfunction contributes to sensory deficits inSYNGAP1haploinsufficiency with important implications for identifying therapeutic targets.