The mutation in the superior gene linked to autism can alter the eye reflex

Reflex Inversion: Counteracting the effects of an SCN2A mutation in the mouse cerebellum (left) helps restore the eye reflex in adolescent mice.

An impaired eye reflex can distinguish children with mutations in SCN2A, one of the genes most strongly linked to autism, according to a new preprint.

The simple test researchers used to analyze the reflex may be a useful clinical biomarker of SCN2A-related autism, says Alfred George, a professor and chairman of pharmacology at Northwestern University in Chicago, Illinois, who was not involved in the work. This has potential uses for diagnosis and as a reading for therapies.

Mice with a mutation in SCN2A also display the impaired reflex, which became more typical after the researchers counteracted the effects of the mutations in the adolescent animals.

This gives us some hope that, if and when such a therapy enters clinical trials, it could be beneficial, even for those children who have lived with an SCN2A disorder for some time, says co-lead researcher Kevin Bender, professor associate of neurology at the University of California, San Francisco.

Up to 90% of autistic children have atypical responses to sensory stimuli. Research into the neural circuitry underlying these sensitivities has generally focused on the forebrain, which holds the brain’s major sensory processing centers. But such sensitivities may also involve reflexes that fire before sensory information reaches the forebrain, according to a 2015 study.

The new study investigated the vestibulo-ocular reflex, which helps people maintain a fixed gaze whenever the head moves, triggering eye movements in the opposite direction of the head. In neurotypical children, this reflex is sensitive to fast head movements but less so to slower ones, while in autistic children it tends to be sensitive to both fast and slow movements.

TTo measure this reflex in 5 children with loss-of-function variants in SCN2A and 11 neurotypical children, Bender and his colleagues developed a lightweight, helmet-mounted, infrared eye-tracking system coupled with motion-sensing electronics. The children wore this device while rolling back and forth in a swivel chair, revealing that the reflex differs between those with and without SCN2A mutations.

Similar differences emerged between SCN2A mice and wildtype mice placed on a rotating platform equipped with an eye tracking device. We could see differences between animals with SCN2A loss and littermates that had normal SCN2A levels, simply by observing how their eyes moved in response to a movement of their head,” says co-lead Guy Bouvier, group leader at the Paris – Saclay Institute of Neuroscience in France.

Mice lacking a copy of SCN2A have previously shown few clear changes in behaviors such as social interaction and repetitive behavior, Bender says. In contrast, the eye movements in these mice were markedly different. It’s the most robust behavioral effect we’ve ever seen in the lab.

Noeuronal activity in the cerebellum mediates the vestibulo-ocular reflex, previous studies suggest. Mice engineered to carry a loss-of-function SCN2A mutation in cerebellar granule cells show impairments in synaptic plasticity, according to the new study.

Specifically, the mutation altered the plasticity between granule cells and Purkinje cells, which connect the cerebellum to other areas of the brain. This, in turn, prevented the synaptic changes that normally regulated the sensitivity of the vestibulo-ocular reflex. The scientists published their findings on the bioRxiv preprint server in June.

Involuntary actions: Neurons in the mouse cerebellum express SCN2A (green) and help control the eye reflex.

“We think this highlights a role of the cerebellum in autism spectrum disorder that is a little less appreciated than it should be. [be]”, says Bouvier. Autism affects the entire brain and the cerebellum strongly interconnects with the social and emotional centers.

Adolescent SCN2A mice displayed typical reflex plasticity after the scientists used a CRISPR-based approach to boost SCN2A expression. This might bode well for a human version of this therapy, but it will be some time before we’re really in that moment, Bender says.

Children with SCN2A loss-of-function mutations typically speak few or no words and have difficulty following instructions. The new vestibulo-ocular reflex testing paradigm appears to be simple to implement, even in patients who are nonverbal or uncomfortable with restraint, says Stephanie Rudolph, assistant professor of neuroscience, psychiatry, and behavioral sciences at the Albert Einstein College of Medicine in New York. York City, which did not participate in this work. It should be determined at what stage of development the vestibulo-ocular reflex test can be evaluated in patients.

Future research should investigate whether the atypical reflex occurs in children with other conditions. There are hints that it may be more common, but a much larger group of children needs to be studied to know for sure, Bouvier says.

It’s not clear whether impairments in this reflex contribute to other aspects of autism, Rudolph notes. However, testing whether reflex regulation ameliorates other behavioral deficits in SCN2A mice is an attractive possibility that should be explored, he says.