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
- transcranial magnetic stimulation
- drug induced
- genome wide
- risk factors
- randomized controlled trial
- intellectual disability
- young adults
- poor prognosis
- traumatic brain injury
- signaling pathway
- endoplasmic reticulum stress
- early onset
- metabolic syndrome
- high fat diet induced
- gene expression
- oxidative stress
- cell death
- transcription factor
- immune response
- dna methylation
- copy number
- genome editing
- long non coding rna
- functional connectivity
- wild type