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Animal models are instrumental to understanding the mechanisms underlying autism spectrum disorder, yet translating human behavioral phenotypes remains challenging. Wang et al. leverage a conserved sensorimotor reflex to elucidate synaptic deficits in S cn2a haploinsufficiency and pilot novel rescue strategies. [ABSTRACT FROM AUTHOR]

Children diagnosed with autism spectrum disorder (ASD) commonly present with sensory hypersensitivity or abnormally strong reactions to sensory stimuli. Such hypersensitivity can be overwhelming, causing high levels of distress that contribute markedly to the negative aspects of the disorder. Here, we identify a mechanism that underlies hypersensitivity in a sensorimotor reflex found to be altered in humans and in mice with loss of function in the ASD risk-factor gene SCN2A. The cerebellum-dependent vestibulo-ocular reflex (VOR), which helps maintain one's gaze during movement, was hypersensitized due to deficits in cerebellar synaptic plasticity. Heterozygous loss of SCN2A -encoded Na V 1.2 sodium channels in granule cells impaired high-frequency transmission to Purkinje cells and long-term potentiation, a form of synaptic plasticity important for modulating VOR gain. VOR plasticity could be rescued in mice via a CRISPR-activator approach that increases Scn2a expression, demonstrating that evaluation of a simple reflex can be used to assess and quantify successful therapeutic intervention. [Display omitted] • Vestibulo-ocular reflex (VOR) is hypersensitized by SCN2A loss of function (LoF) • Hypersensitivity is present in children with SCN2A LoF and Scn2a + / − mouse models • VOR gain cannot be reduced in Scn2a +/− mice due to cerebellar plasticity deficits • VOR gain plasticity can be rescued with a CRISPR-activator-based therapeutic Impaired function in the sodium channel gene SCN2A is a major risk factor for autism spectrum disorder. Here, Wang and colleagues show that heterozygous loss of SCN2A in the cerebellum alters reflexive eye movements in both mouse and man and that a translatable gene therapy rescues such movements in mouse. [ABSTRACT FROM AUTHOR]