Microglial Lyn Kinase-TRPV4 axis mediates social deficits in a maternal immune activation model.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition influenced by both genetic and environmental factors. Among these, maternal immune activation (MIA) has emerged as a critical environmental contributor, though the underlying mechanisms remain poorly understood. In this study, we employed both in vivo and in vitro models to investigate the role of TRPV4 activation in microglia within the context of MIA. In vitro, microglia derived from human cell lines and neonatal murine brains, when stimulated by high dose lipopolysaccharide (LPS), exhibit calcium influx that is TRPV4-dependent and TLR4-independent. We next found that microglia could respond to low dose LPS, in the absence of Lyn kinase; Lyn was increasing the threshold for TRPV4 responsiveness to LPS. To translate these findings to an in vivo MIA model, we compared ASD behaviors in the progeny and found that if TRPV4 was inhibited or microglia depleted in the progeny, autistic behaviors decreased significantly. Notably, MIA in Lyn knockout mice significantly exacerbated ASD-like behaviors compared to WT MIA, and critically, treatment of Lyn−/− MIA progeny with a TRPV4 inhibitor reversed these effects on behavior. These findings indicate that the Lyn kinase-TRPV4 signaling axis, acting through complementary yet opposing functions, is a central regulator of microglial activation and ASD-related pathology following maternal immune challenge. This pathway may therefore represent a compelling therapeutic target for ASD.