Short-term immunosuppressive therapy briefly restores autism-like brain changes in adult mice

A new mouse study led by UCLA Health suggests that inflammation during pregnancy can trigger autism-like changes in offspring, but also that those brain and behavior effects may be rapidly but temporarily reversible in adulthood with a short-term dose of the immunosuppressive drug rapamycin.

Even mild inflammation during mid-pregnancy has been shown to result in offspring autism-like symptoms, abnormal brain growth, seizures and heightened sensitivity to everyday sensory input that persists into adulthood.

In the study published in the journal Nature Communications, UCLA researchers found that a single dose of the drug rapamycin significantly improved brain signaling and behavior symptoms in these offspring within about two hours, a time too short to correct underlying physical brain changes created by the maternal inflammation.

The study did not identify rapamycin as a viable treatment for these symptoms in humans given its temporary effects and potential for toxicity from repeated doses. Instead, researchers said the drug's effects revealed new therapeutic targets for the development of future treatments.

The level of functional normalization achieved over this short time suggests new mechanisms by which possible treatments may act. 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."

Dr. Harley Kornblum, Study Senior Author and Director, Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California - Los Angeles Health Sciences

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.

Additionally, rapamycin has been shown in previous mouse autism studies to improve symptoms by suppressing an overactive pathway that signals cell growth and proliferation, known as the mTOR pathway.

What was less clear was 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.

In this study, researchers 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, which was too quick to be explained by the kind of physical rewiring of brain synapses that typically takes longer.

 "These results reframe how autism-associated symptoms might be treated. 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," said the paper's first author Dr. Janel Le Belle, an associate professor in the UCLA Department of Neurosurgery.

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.

Co-senior author and professor in the UCLA Department of Neurosurgery, Dr. Neil Harris, cautioned that they also found 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.