Calcitriol Modulates Hippocampal Axon Guidance Through Enhanced EfnA4‐Mediated PI3K/AKT Signaling in an Autism Mouse Model

Abstract

ABSTRACTAimsAutism spectrum disorder (ASD) is a complex neurodevelopmental condition arising from the interplay of genetic predispositions and environmental influences. Recent studies have suggested that vitamin D (VitD) supplementation play a role in reducing the risk of ASD and alleviating some of its core symptoms. However, variations in individual responses to VitD due to biological heterogeneity have led to inconsistent clinical outcomes, and the precise molecular mechanisms through which VitD might exert its effects on ASD remain poorly understood.MethodsWe investigated the effects of calcitriol, the biologically active form of VitD, on ASD‐associated phenotypes in BTBR mice, a well‐established autism model. Behavioral assessments were used to evaluate social and repetitive behaviors. Mechanistic insights were obtained through RNA sequencing, immunohistochemistry, biochemical assays, and stripe guidance assays.ResultsCalcitriol supplementation significantly improved autism‐like behaviors in BTBR mice, alleviating hippocampal hypoplasia and correcting axon guidance abnormalities. These effects were mediated by modulation of the EfnA4‐PI3K signaling pathway in hippocampal neural progenitor cells and other brain regions, highlighting its role in neurodevelopmental processes.ConclusionOur findings demonstrate that calcitriol targets axon‐guidance‐related signaling pathways, providing a theoretical framework and potential clinical strategy for targeted ASD interventions.