“Timing is everything,” is not an exaggeration when it comes to neurodevelopmental disorders and optimal therapeutic interventions. A new mouse model study has identified a critical time window ranging to five weeks after birth when disruptions in the cerebellum affect social deficits—a hallmark diagnostic criteria of autism spectrum disorders (ASD). The study showed blocking an aberrant signaling pathway important in neurodevelopment during the first five weeks of life prevents ASD from developing in mice.

Peter Tsai, PhD, professor in the departments of neurology, neuroscience, and pediatrics and psychiatry, at the University of Texas Southwestern Medical Center, and senior author of the study said, “In these investigations, we demonstrate that there are critical periods during which autism-relevant behaviors are developed and that there appears to be divergent periods depending on the specific behavior.”

Animal models bearing mutations in many ASD-linked genes show impaired development and function of the cerebellum—a densely packed ovoid structure at the back of the brain that is about one-tenth its size but houses more neurons than the rest of the brain. Cerebellar pathology is also consistently observed in autopsy studies on patients with ASD.

Yet, the lack of clear understanding of the neurodevelopmental time window (critical period) when structural and functional abnormalities in the cerebellum impact ASD-relevant behavioral hallmarks, has prevented the application of these biological insights in developing optimized therapies for ASD. At present, there are no targeted therapies for ASD.

In the study published in the Journal of Neuroscience (“A critical period for development of cerebellar-mediated autism-relevant social behavior“), Tsai and his team show treatment of model mice with rapamycin up to five weeks following birth is sufficient to ensure the development and maintenance of normal social behaviors whereas treatment with the drug, even into adulthood, does not remedy repetitive behaviors and behavioral inflexibility—the other diagnostic criteria for ASD.

“Treatment in a time period in the mouse comparable to adolescence [in humans] results in long-lasting normalization of social behaviors, albeit with few if any benefits noted for repetitive or inflexible behaviors,” said Tsai.

Rapamycin inhibits mTOR signaling—a pathway important in regulating cellular metabolism, growth, division, and survival—that is overactive in people and animal models with TS (tuberous sclerosis). TS is a neurodevelopmental disorder commonly diagnosed in the autism spectrum.

“For the neurodevelopmental disorder, TS, in which the key signaling pathway, mTOR, [mechanistic target of rapamycin] is disrupted, agents targeting this abnormal signaling have shown significant benefits clinically and in models of this disorder,” explained Tsai.

The model mice that the team used in this study were male and harbored mutations in the gene Tsc1 (Tuberous Sclerosis Complex 1) selectively in the large Purkinje cells in the cerebellum.

“These data show a mechanistic basis for these phenotypes which should inform further biological study and potential treatment strategies. Taken together, these data point to the presence of distinct critical periods for specific behaviors and potential mechanistic underpinnings for them,” said Tsai.

Since specific functional capacities of the brain and particular neurodevelopmental disease symptoms develop during critical periods, administering a targeted intervention during the critical period could prevent the disorder from ever emerging, eliminating the burden of life-long treatments.

“Intriguingly from a therapeutic context, this disorder is often diagnosed prenatally. Thus the potential for early therapy to treat this disorder and potentially reduce or prevent the sequelae of neurodevelopmental phenotypes (including autism-relevant behaviors) associated with the disorder have therapeutic appeal,” said Tsai.

Tsai added, “As with all medications, medications targeting this [mTOR] pathway are not without their significant side effects. If one could define the time windows during which abnormal neurodevelopmental phenotypes can develop, one could potentially inform when therapy would have to be administered to treat these developmental phenotypes, specifically restricting the timing of treatments to those critical periods. This would minimize the potential side effects of available therapies.”

In future studies, the team will further delineate the critical periods and their circuit level underpinnings, in addition to leveraging these findings to inform treatment of autism-relevant behaviors and other neurodevelopmental disorders.

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