Mouse Study IDs Potential Brain Mechanism Behind Autism Traits

A new study has identified brain circuitry that plays a key role in the dysfunctional social, repetitive, and inflexible behavioral differences that characterize autism spectrum disorders (ASD).
The findings, published in the journal Nature Neuroscience, could lead to new treatments for people with ASD.

The Centers for Disease Control and Prevention estimate that about 1 in 54 children in the U.S. have ASD, 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, said Peter Tsai, M.D., Ph.D., assistant professor in the departments of neurology and neurotherapeutics, neuroscience, pediatrics, and psychiatry at the University of Texas (UT) Southwestern Medical Center and a member of the Peter O’Donnell Jr. Brain Institute.
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, Tsai said.
Recent studies by Tsai and his colleagues have shown that inhibiting activity in a region of the cerebellum known as Rcrus1 can cause altered social and repetitive/inflexible behaviors reminiscent of ASD in mice.
Their studies also found that stimulation of this area could rescue social behaviors in an ASD-relevant model but was unable to improve repetitive or inflexible behaviors. These combined findings suggest that additional regions of the cerebellum might also regulate repetitive and/or inflexible behaviors.
However, exactly how these brain regions might regulate these ASD-relevant behaviors has remained unknown. To learn more about the brain circuitry controlling these behaviors, Tsai and a research team worked with mice genetically engineered to reduce the activity of Purkinje cells, specialized cells that turn down the activity of other brain regions.

When they looked at the rest of the brain, they saw increased activity in the medial prefrontal cortex (mPFC), another region previously implicated in ASD. Behavioral tests revealed that these rodents displayed characteristic social and repetitive/inflexible behaviors similar to ASD. When the team inhibited mPFC activity in these animals, both social impairments and repetitive/inflexible behaviors improved.
Since 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 discovered connections specifically between Rcrus1 and the mPFC in these animals, with decreased Rcrus1 activity leading to increased mPFC activity.
Further studies 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.
Since these experiments were able to improve dysfunctional social and repetitive/inflexible behaviors 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,” Tsai said.
Source: UT Southwestern Medical Center

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