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bioRxiv · 10.1101/2022.12.06.519295

Syngap1 Regulates Cortical Circuit Assembly by Controlling Membrane Excitability

Arora, V.·Michaelson, S.·Aceti, M.·Klinik, M.·Miller, C.·Rumbaugh, G.
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Abstract

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. HighlightsO_LISyngap1 cell-autonomously tunes cortical pyramidal neuron IME in vivo C_LIO_LISyngap1-IME is regulated in part by control of neuronal potassium currents C_LIO_LISyngap1 enhancement of IME drives dendritic maturation in pyramidal cells C_LIO_LISyngap1 tuning of IME-regulated dendritic maturation promotes circuit assembly C_LI

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Arora, V., Michaelson, S., Aceti, M., Klinik, M., Miller, C., Rumbaugh, G.. 2022-12-06. Syngap1 Regulates Cortical Circuit Assembly by Controlling Membrane Excitability. https://doi.org/10.1101/2022.12.06.519295

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