Investigating the physiological and molecular effects of inflammation episode on neurodevelopment and ASD risk

Neurodevelopmental disorders (NDDs) are a group of conditions including autism spectrum disorders (ASD). These disorders affect brain development and are characterized by social and cognitive deficits with onset in early life and long-lasting consequences. Several studies already demonstrated the genetic contribution to NDD risk, while more recently a strong impact of environmental factors, such as fever or other inflammatory insults, has emerged underlining a multifactorial origin. More specifically, maternal infections, prenatal and early postnatal inflammation are well-established risk factors for these disorders. Astrocytes, essential glial cells involved in synapse formation and refinement, can respond to inflammatory environments, potentially disrupting neuronal network homeostasis. However, the impact of a prenatal inflammatory episode on astrocyte generation and phenotype remains largely unexplored. In the brain, the innate immune molecule Pentraxin3 (PTX3), produced by astrocytes, supports the maturation of excitatory synapses. Its expression is upregulated by inflammatory stimuli in both mouse models and human iPSC-derived astrocytes. Using a maternal immune activation (MIA) mouse model to simulate bacterial or viral infections with LPS or Poly (I:C), respectively, we found that astrocytes from MIA offspring retain a distinct molecular signature corresponding to the specific inflammatory stimulus used, even when analysed three weeks after the maternal inflammatory event. When co-cultured with wild-type neurons, MIA-derived astrocytes impair synapse formation and functional maturation. Additionally, we observed that MIA alters PTX3 expression in the cerebral cortex—but not in the hippocampus—of offspring during the first and second postnatal weeks, a critical period for synapse development. Interestingly, the number of astrocytes is also specifically altered in the cerebral cortex during this stage. These findings reveal, for the first time, that maternal immune activation and prenatal inflammation lead to astrocytes’ long-term developmental alterations. Considering the well-established role of disruptions in synaptic structure and function as key drivers of neurodevelopmental disorders — a concept that underlies the term “synaptopathies”— it is crucial to investigate how pre- and perinatal inflammation may contribute within a synaptopathy framework. By exploiting the Shank3 mouse model, which has been instrumental in elucidating synaptic deficits associated with ASD, we showed that a single perinatal exposure to LPS was sufficient to elicit a selective reduction of excitatory synapses in the hippocampal CA1 region during adolescence, which we traced back to an increase in microglial phagocytic activity. A focused exploration of astrocytes’ contributions to disease mechanisms in this genetic context is particularly warranted.