Tag: Mental health

The results of a preclinical study led by UCLA Health researchers suggest that inflammation during pregnancy in mice can trigger autism-like brain and behavior changes in offspring, and that the effects may be rapidly but temporarily reversible in adulthood with a short-term dose of the immunosuppressive drug rapamycin.

The study showed that a single dose of rapamycin rapidly improved changes including brain overactivity, seizure risk, sensory sensitivity, repetitive behaviors, and abnormal brain functional network organization. Rapamycin itself is not considered a viable candidate for human therapy, as the effects of the drug were found to be temporary, with repeated dosing losing efficacy, and repeated use also having the potential for toxicity. However, the researchers said the study findings indicate that some autism-related brain changes may still be treatable in adulthood, and point to possible therapeutic approaches that target the underlying pathway rather than only symptoms.

“These results reframe how autism-associated symptoms might be treated,” said Janel Le Belle, PhD, an associate professor in the UCLA Department of Neurosurgery. “If the adult brain remains capable of functional normalization, then some features of autism may be successfully addressed without needing to correct underlying structural differences.” Le Belle is first author of the researchers’ published paper in Nature Communications, titled “Acute rapamycin treatment reveals distinct mechanisms of dysfunction in a maternal inflammation mouse model.”

Neurodevelopmental disorders result from the disruption of brain development in utero or in early life, with genetic, environmental, epigenetic, and immunological factors all potential contributors to complex pathogenesis, the authors wrote. Previous studies have shown that offspring of mothers who experience inflammation while pregnant have a higher likelihood of developing autism-associated traits such as repetitive behaviors and difficulty with social interaction, as well as brain overgrowth and disrupted sensory processing that continue into adulthood. “Maternal inflammatory response (MIR) during early mouse gestation induces a cascade of physiological and behavioral changes associated with autism spectrum disorder (ASD),” they stated.

Rapamycin has been shown in previous mouse autism studies to improve symptoms by suppressing an overactive mTOR pathway that signals cell growth and proliferation. What has been less clear is whether these brain changes could still be modifiable in adulthood, and whether rapamycin’s benefits came from long-term structural repair or faster functional changes. “We wanted to understand the mechanisms that underlie the effects of adult mTOR inhibition, where treatment isn’t aimed at preventing or reversing structural brain abnormalities,” the team stated.

For their newly reported study the scientists exposed pregnant mice to a mild inflammatory trigger early in gestation at a dose that was too low to make the mothers significantly ill. The resulting offspring went on to develop chronic brain and body-wide inflammation, mild brain overgrowth, overactive cell-signaling in the mTOR pathway, disorganized brain functional network connectivity and behaviors associated with autism.

When researchers gave adult offspring a single dose of rapamycin they found rapid improvement across nearly every measure. Neurons that had been firing abnormally calmed down, susceptibility to seizures dropped, brain regions that had been miscommunicating reorganized into more typical patterns and repetitive behaviors and sensory over-responsivity eased. These changes occurred within roughly two hours of drug administration, which was too rapid to be explained by the kind of physical rewiring of brain synapses that typically takes longer.

“The level of functional normalization achieved over this short time suggests new mechanisms by which possible treatments may act,” said the study’s senior author Harley Kornblum, MD, PhD, director of the UCLA Intellectual and Developmental Disabilities Research Center in the Semel Institute for Neuroscience and Human Behavior. “It suggests the adult brain may be more adaptable than we assumed, even when the underlying structural changes from early development are still there. This points us toward the brain’s functional circuitry, not just its physical structure, as a target for future treatment approaches.”

To understand the mechanisms of rapid rapamycin effects, researchers examined gene activity in brain cells before and after treatment. They found that rapamycin reversed abnormal expression of genes tied to autism, epilepsy and ion channel function, particularly in excitatory neurons, suggesting the drug works by quickly rebalancing brain cell excitability rather than by repairing structural brain differences.

The findings suggest that mTOR pathway activity, brain network organization and neuronal excitation levels as potential targets for future therapies aimed at specific autism symptoms such as sensory over-responsivity, a common but difficult-to-treat symptom of autism. “Our findings demonstrate that mTOR dysregulation drives dysfunctional brain development in MIR offspring but the adult brain remains amenable to rapid functional normalization, rescuing core and comorbid ASD associated brain and behavior phenotypes,” the authors stated.

Co-senior author and professor in the UCLA Department of Neurosurgery, Neil Harris, PhD, cautioned that the results showed the treatment effects to be temporary and that daily dosing produced tolerance over several weeks. This, along with rapamycin’s high potential for toxicity and the fact that these studies were performed in mice, makes it unsuitable for broad use in humans. “This points toward new therapeutic targets like sensory circuit neuromodulation or balancing neuronal inhibition and excitation, rather than toward rapamycin itself as a treatment,” Harris said. As the authors further commented in their paper, “Restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing multiple ASD phenotypes.”

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