A UCLA Health study in mice found that inflammation during pregnancy can cause lasting autism-like changes in offspring. The researchers also found that many of the resulting brain and behavioral effects could be rapidly ameliorated in adulthood, albeit temporarily, by a single dose of the immunosuppressive drug rapamycin.
Previous studies have shown that even mild inflammation during the second trimester can affect offspring development. Reported effects include autism-like behavior, abnormal brain growth, seizures, and hypersensitivity to normal sounds, touch, and other sensory experiences. These effects can continue into adulthood.
In a new study published in nature communicationsUCLA scientists found that a single dose of rapamycin improved brain communication and behavior in affected mice in about two hours. The response was too rapid for the drug to repair the fundamental physical changes in the brain caused by the mother’s inflammation.
rapid but temporary brain response
The researchers stressed that rapamycin should not be considered a practical treatment for these conditions in people. Its effects are temporary and can become toxic with repeated use, and the study was conducted in mice. Rather, the rapid response helped uncover biological processes that could guide the development of safer and more targeted treatments.
“The level of functional normalization achieved in this short period of time suggests new mechanisms by which potential treatments may act,” said Harley Kornbloom, Ph.D., lead author of the study and director of the UCLA Center for Intellectual and Developmental Disorders Research in the Semel Institute for Neuroscience and Human Behavior. “This suggests that the adult brain may be more adaptive than we had assumed, even if fundamental structural changes from early development are still present. This points to a focus on the brain’s functional circuitry, not just its physical structure, as a target for future therapeutic approaches.”
Previous research has found that children born to mothers who experience inflammation during pregnancy may be more likely to develop traits associated with autism. These include repetitive behaviors, challenges with social interactions, enlarged brain growth, and changes in sensory processing that persist into later life.
Rapamycin also produced improvements in previous mouse studies on autism. The drug works in part by reducing the activity of the mTOR pathway, a biological signaling system that regulates cell growth and proliferation. Excessive mTOR activity is associated with some autism-related symptoms.
But scientists didn’t know whether the effects on the brain caused by maternal inflammation might change in adulthood. It was also unclear whether rapamycin worked by gradually repairing brain structure or by producing more rapid changes in the function of brain circuits.
Modeling inflammation during pregnancy
To study, the researchers exposed pregnant mice to a mild inflammatory stimulus during the first trimester of pregnancy. The dose was low enough that the mother did not become seriously ill.
Their offspring then developed persistent inflammation in both the brain and the rest of the body. They also showed mild brain overgrowth, excessive signaling through the mTOR pathway, disorganized communication across functional brain networks, and behaviors associated with autism.
The researchers then gave the adult children a single dose of rapamycin. They found improvements in almost every measure they looked at.
Neurons that were abnormally active began firing more normally. The animals were less likely to have seizures. The brain regions that were not communicating properly shifted to a more typical pattern. Repetitive behaviors, sensory sensitivities, and hyperreactivity to sensory input were also reduced.
All these changes appeared within about 2 hours. Because the physical rebuilding of brain synapses generally takes time, the scientists concluded that rapamycin was altering brain function rather than rebuilding the underlying brain structure.
“These results reshape the way we treat symptoms associated with autism. If we can preserve the adult brain’s ability to normalize function, we may be able to successfully address some of the features of autism without modifying the underlying structural differences,” said lead author Dr. Janelle Le Bell, associate professor of neurosurgery at UCLA.
Rebalancing neuronal activity with rapamycin
To find out why the drug worked so quickly, the researchers analyzed gene activity in brain cells before and after treatment.
Rapamycin reversed abnormal patterns of gene expression involved in autism, epilepsy, and ion channel function. The strongest effects appeared on excitatory neurons that stimulate activity in brain networks.
This suggests that the drug rapidly restored a healthier balance of neuronal excitability, rather than repairing structural differences formed early in development.
The results point to several potential targets for future treatments, including mTOR pathway activity, brain network organization, and balance of excitability among neurons. Such an approach could address certain autism symptoms, such as sensory overreactivity, which is common and often difficult to treat.
Why rapamycin is not a cure
Co-senior author Dr. Neil Harris, professor of neurosurgery at UCLA, cautioned that the effects are short-lived. The researchers also found that the daily treatment became less effective after a few weeks as the mice developed a tolerance.
These limitations, combined with rapamycin’s potential toxicity and the fact that its findings were derived from animal studies, make the drug unsuitable for widespread use in humans.
“This points not to rapamycin itself as a treatment, but to new therapeutic targets such as neuromodulation of sensory circuits and the balance of inhibition and excitation in neurons,” Harris said.
Important points
- In mice, inflammation during pregnancy causes long-term, autism-like changes in brain activity and behavior, showing that early immune disruption can influence brain development into adulthood.
- A single dose of rapamycin rapidly improved brain overactivity, seizure susceptibility, sensory sensitivities, repetitive behaviors, and abnormal communication between brain networks.
- This rapid response suggests that some of the functional changes associated with autism may remain modifiable into adulthood, even if physical differences in brain structure still exist.
- The effects of rapamycin are temporary and diminish with repeated treatments. Although it is unlikely to become a widely used treatment due to its toxicity and the animal-based nature of the research, the discovery could help scientists identify safer therapeutic targets.
