Syngap1 Regulates Cortical Circuit Assembly by Controlling Membrane Excitability

Summary Gene expression intersects with neural activity to produce cortical circuits during brain development. However, the cell biological mechanisms linking gene expression to activity-dependent cortical circuit assembly remain unclear. Here, we demonstrate in mice that a newly discovered function of the neurodevelopmental disorder gene, Syngap1 , is to cell-autonomously control intrinsic membrane excitability (IME) in developing cortical glutamatergic neurons. Syngap1 regulation of IME was mechanistically linked to wiring of a cortical circuit motif required for sensory processing and behavioral action. Restoring depressed IME in Syngap1 deficient neurons through genetic targeting of hyper-functional potassium currents unleashed deficient dendritic morphogenesis in upper lamina sensory cortex pyramidal neurons. Furthermore, enhancing dendritic morphogenesis was sufficient to stimulate assembly of translaminar feed-forward excitatory circuit motifs. Thus, Syngap1 promotes excitatory circuit assembly during cortical development by maintaining IME in a range that enables trophic neuronal activity to maximize pyramidal cell somatodendritic maturation and subsequent synapse formation. Highlights Syngap1 cell-autonomously tunes cortical pyramidal neuron IME in vivo Syngap1 -IME is regulated in part by control of neuronal potassium currents Syngap1 enhancement of IME drives dendritic maturation in pyramidal cells Syngap1 tuning of IME-regulated dendritic maturation promotes circuit assembly