EARLY ONSET OF CEREBELLAR AND PERIPHERAL INFLAMMATION IN CNTNAP2 AND SHANK3B MOUSE MODELS OF AUTISM

Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by deficits in social interaction and communication, as well as restricted interests and repetitive behaviors. Increasing evidence indicates that neuroinflammation and immune dysregulation, particularly involving microglia, are implicated in ASD pathophysiology. We previously showed that altered cerebellar microglia activation correlates with increased inflammation and cytokine production in both in adult Cntnap2 and Shank3b mutant mice, two established models of ASD. Treatment with anti-inflammatory drugs reduces neuroinflammation and improves social and motor behaviors in adult mutant mice, supporting a causal role for impaired cerebellar microglial function in ASD pathogenesis. However, the time course of cerebellar inflammation onset in Cntnap2 and Shank3b mutant mice remains unknown. To address this issue, we used RT-qPCR and immunohistochemistry to quantify inflammatory cytokine expression and microglial density and morphology in the cerebellum, hippocampus, and cerebral cortex of Cntnap2^−/−, Shank3b^−/− , and respective control mice at early postnatal stages (P1-P7). In parallel, RT-qPCR was used to assess the temporal profile of cytokine expression in peripheral immune organs (spleen and bone marrow) in mutant and control mice at the same developmental stages. Preliminary data indicate that peripheral and cerebellar inflammation, together with microglial activation, emerge early (P1) in Cntnap2-/- mice, whereas a delayed inflammatory response (P7) is observed in Shank3b-/- mice. These findings support the existence of distinct developmental mechanisms that converge toward similar ASD-like phenotypes. Overall, our results strengthen the hypothesis that both cerebellar and peripheral inflammation play a crucial role in ASD pathogenesis.