Disruption of Myelin-Associated Glycoprotein Activity Drives Aberrant Cerebellar Neurodevelopment and Autism-Like Behaviors.

Abstract

Immune-mediated mechanisms have emerged as important contributors to neurodevelopmental vulnerability in a subset of autism spectrum disorder (ASD) cases. Circulating IgG antibodies against myelin-associated glycoprotein (MAG) have been reported in individuals with ASD and their mothers; however, the pathogenic relevance of these antibodies and the contribution of MAG signaling to neurodevelopment remain unclear. Here, we investigated whether disruption of MAG function during early postnatal life is sufficient to alter cerebellar development and induce ASD-relevant behavioral alterations. Using complementary genetic and immunological approaches, we show that constitutive deletion of Mag or transient postnatal blockade with a function-blocking anti-MAG antibody induces region-specific alterations in cerebellar development. MAG disruption results in excessive proliferation of granule cell precursors followed by delayed, region-restricted neuronal death, together with persistent abnormalities in Purkinje neuron number and dendritic maturation. These structural changes occur in the absence of major or persistent demyelination, consistent with dysregulation of myelin-associated developmental signaling rather than myelin loss. Importantly, early postnatal passive immunization with anti-MAG IgG is sufficient to induce significant impairments in social communication, sociability, and social recognition, recapitulating core behavioral domains relevant to ASD. Together, these data provide experimental evidence that immune-mediated interference with a myelin-associated signaling molecule can disrupt cerebellar development during critical postnatal windows and produce long-lasting behavioral consequences. Our findings identify MAG as a previously underappreciated regulator of neurodevelopment and support a model in which antibody-mediated perturbation of myelin-derived instructive signaling contributes to ASD-relevant phenotypes, aligning with emerging frameworks of immune-linked neurodevelopmental vulnerability. HighlightsO_LIDisruption of myelin-associated glycoprotein (MAG) activity during early postnatal life alters cerebellar development in a region-specific manner. C_LIO_LIGenetic deletion or antibody-mediated blockade of MAG function induces granule cell dysregulation and Pkn structural abnormalities without overt demyelination. C_LIO_LIPassive immunization of anti-MAG antibodies is sufficient to induce autism-like behavioral phenotypes, supporting a causal immune-mediated mechanism. C_LIO_LIThese findings identify myelin-associated signaling as a novel contributor to neurodevelopmental dysfunction and align with the maternal autoantibody-related ASD framework. C_LI