Learning the wiring for autism spectrum disorder

An international research team, led by the University of Texas Southwestern Medical Center (UT Southwestern), has identified brain circuitry that plays a key role in the dysfunctional social, repetitive and inflexible behavioural differences that characterise autism spectrum disorder (ASD). The team’s findings, published in the journal Nature Neuroscience, could lead to new therapies for these relatively prevalent disorders.

ASD comprises a broad range of neurodevelopmental conditions thought to be caused by a combination of genetic and environmental factors. Although researchers have identified some key genes and pathways that contribute to ASD, the underlying biology of these disorders remains poorly understood. That’s according to Dr Peter Tsai, an assistant professor at UT Southwestern and a member of the Peter O’Donnell Jr. Brain Institute.

Dr Tsai stated that one key brain region that’s been implicated in ASD dysfunction is the cerebellum — part of the hindbrain in vertebrates that holds about three-quarters of all the neurons in the body and has traditionally been linked with motor control. Recent studies by Dr Tsai and his colleagues have demonstrated that inhibiting activity in a region of the cerebellum known as Rcrus1 can cause altered social and repetitive/inflexible behaviours reminiscent of ASD in mice. Their work also found that stimulation of this area could rescue social behaviours in an ASD-relevant model but was unable to improve repetitive or inflexible behaviours. Together, these studies suggested that additional regions of the cerebellum might also regulate repetitive and/or inflexible behaviours.

In addition, how these cerebellar regions might regulate these ASD-relevant behaviours remained unknown. To learn more about the brain circuitry controlling these behaviours, Dr Tsai and his colleagues worked with mice genetically engineered to reduce the activity of Purkinje cells — specialised cells that turn down the activity of other brain regions. When they examined the activity of the rest of the brain, they saw increased activity in the medial prefrontal cortex (mPFC) — another region previously implicated in ASD. Behavioural tests showed that these animals displayed characteristic social and repetitive/inflexible behaviours reminiscent of ASD. When the researchers inhibited mPFC activity in these animals, both social impairments and repetitive/inflexible behaviours improved.

Because the cerebellum and the mPFC are on opposite ends of the brain, the team used microscopic imaging to trace how these regions are linked. They found connections specifically between Rcrus1 and the mPFC in these animals, with decreased Rcrus1 activity leading to increased mPFC activity. Further investigation showed that connectivity in this region wasn’t just disrupted in these particular mice. It also existed in about a third of 94 different mouse lines carrying autism-related mutations and in two independent cohorts of people with ASD.

Looking further to better determine the anatomical connections between these regions, the researchers saw that signals from Rcrus1 appear to be routed to the mPFC through an area known as the lateral nucleus; however, modulation of this region was only sufficient to improve social behaviours in their genetic mouse model while repetitive/inflexible behaviours remained abnormal. Thus, the scientists interrogated other cerebellar regions and found that modulation of another ASD-implicated cerebellar region, the posterior vermis, results in improvement in repetitive and inflexible behaviours. They then asked whether this cerebellar region also targets the mPFC and found that both posterior vermis and Rcrus1 converge on the mPFC through another intermediate region, the ventromedial thalamus.

Each of these regions could play a key role in potential future therapies for ASD, according to Dr Tsai. And because the team’s experiments could improve dysfunctional social and repetitive/inflexible behaviours even in adult animals, it raises the possibility that therapies that target this circuit in humans might be able to improve ASD-related dysfunction even into adulthood.

“Just as an electrician can repair a home’s wiring once he or she understands the wiring diagram, these findings give us potential hope for improving dysfunctional activity in the circuits involved in ASD,” Dr Tsai said.

Image credit: ©stock.adobe.com/au/pathdoc

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