Severe postnatal infections increase autism risk in genetically predisposed males: Mechanistic and therapeutic implications

Emerging evidence indicates that environmental insults, particularly immune activation early in life, can be a risk factor for neuropsychiatric disorders. Early-life environmental factors, especially immune system activation, can amplify the effects of genetic vulnerability in shaping neuropsychiatric outcomes. Tuberous sclerosis complex (TSC), a genetic disorder affecting ~1 in 6,000 individuals, carries a markedly elevated risk for autism spectrum disorder (ASD), with prevalence rates of 40-60% compared with 1-2% in the general population. In this study, we investigated whether early postnatal immune activation influences social and cognitive phenotypes in Tsc2^+/- mice, a model of TSC.

Our findings show that immune challenges during early development produced striking social impairments specifically in males, including deficits in social memory and atypical communication. Mechanistically, these alterations were linked to dysregulated mammalian target of rapamycin (mTOR) dependent interferon signaling and microglial dysfunction. Remarkably, treatment with rapamycin both prevented and durably reversed the social memory deficits, while genetic deletion of the interferon receptor IFNAR1 conferred similar protection against the adverse effects of early immune activation in male Tsc2^+/- mice.

To determine the relevance to humans, we analyzed medical records from over three million children. We found that severe infections requiring hospitalization during early life were significantly associated with later ASD diagnosis in boys but not in girls, paralleling the sex-specific vulnerability observed in mice. Together, these findings uncover a mechanism through which severe postnatal infections and genetic predisposition converge to disrupt social and communication development. They also point to potential therapeutic opportunities targeting mTOR and interferon pathways in neurodevelopmental and neuropsychiatric disorders.

Manuel F. López Aranda, Ph.D., is a Distinguished Researcher at the University of Málaga (Spain) under the Beatriz Galindo Program. He earned his Ph.D. in Neuroscience from the University of Málaga and completed postdoctoral training at the University of California, Los Angeles (UCLA), where he later served as Assistant Project Scientist. His research investigates neurobiological mechanisms of learning and memory deficits in disorders such as Autism Spectrum Disorder and Alzheimer’s disease, with emphasis on microglia and immune activation. He has published in high-impact journals, including Science, Nature Reviews Neuroscience, and Science Advances.