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.
Keyphrases
- high frequency
- autism spectrum disorder
- induced apoptosis
- cell cycle arrest
- attention deficit hyperactivity disorder
- drug induced
- transcranial magnetic stimulation
- randomized controlled trial
- poor prognosis
- genome wide
- signaling pathway
- risk factors
- intellectual disability
- endoplasmic reticulum stress
- crispr cas
- traumatic brain injury
- young adults
- high fat diet induced
- oxidative stress
- early onset
- type diabetes
- long non coding rna
- genome editing
- dna methylation
- binding protein
- skeletal muscle
- cell proliferation
- wild type
- optic nerve