Restoration of excitation/inhibition balance enhances neuronal signal-to-noise ratio and rescues social deficits in autism-associated Scn2a -deficiency

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ABSTRACT Social behavior is critical for survival and adaptation, which is profoundly disrupted in autism spectrum disorders (ASD). Social withdrawal due to information overload was often described in ASD, and it was suspected that increased basal noise, i.e., excessive background neuronal activities in the brain could be a disease mechanism. However, experimental test of this hypothesis is limited. Loss-of-function mutations (deficiency) in SCN2A , which encodes the voltage-gated sodium channel Na V 1.2, have been revealed as a leading monogenic cause of profound ASD. Here, we revealed that Scn2a deficiency results in robust and multifaceted social impairments in mice. Scn2a -deficient neurons displayed an increased excitation-inhibition (E/I) ratio, contributing to elevated basal neuronal noise and diminished signal-to-noise ratio (SNR) during social interactions. Notably, the restoration of Scn2a expression in adulthood is able to rescue both SNR and social deficits. By balancing the E/I ratio and reducing basal neuronal firing, an FDA-approved GABA A receptor-positive allosteric modulator improves sociability in Scn2a -deficient mice and normalizes neuronal activities in translationally relevant human brain organoids carrying autism-associated SCN2A nonsense mutation. Collectively, our findings revealed a critical role of the Na V 1.2 channel in the regulation of social behaviors, and identified molecular, cellular, and circuitry mechanisms underlying SCN2A -associated disorders. HIGHLIGHTS Na V 1.2 deficiency leads to pronounced social deficits in mice. Na V 1.2 deficiency results in an overall enhanced E/I ratio, elevated basal neuronal activity, and impaired signal-to-noise ratio. Both the enhanced E/I ratio and impaired sociability are reversible through the restoration of Na V 1.2 expression in adulthood. Targeted restoration of Na V 1.2 in striatum-projecting neurons rescues social impairments. GABA transmission is reduced in both mouse and human organoid models of SCN2A deficiency, and acute systemic administration of GABA A receptor-positive allosteric modulators restores sociability. Graphical abstract Graphical abstract: Severe Scn2a deficiency leads to a predominate decrease in GABA transmission with an overall enhanced E/I ratio, elevated basal neuronal activity, impaired SNR, and social deficits in adult Na V 1.2-deficient mice.

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