Effects of MDGA2 Reduction on Synaptic Long-Term Depression and Development in Male Mice

Abstract

MDGA2, an autism-linked synapse organizer, restricts excitatory synaptogenesis by inhibiting neurexin-neuroligin adhesion complexes and BDNF/TrkB signaling. Mdga2+/- mice, modeling autism-associated mutations, show increased excitatory synapse density and hyperexcitation in adulthood, resulting in altered hippocampus-dependent cognition and plasticity. Despite the critical role of synapse organizers in development, the effects of Mdga2 reduction on synaptogenesis, synaptic pruning, and long-term depression (LTD) remain unclear. To address this gap, this study investigated synaptic weakening via LTD induction, spine development across postnatal stages via Golgi-Cox staining, and proteomic alterations in the hippocampus of Mdga2+/- mice. Results reveal that Mdga2 reduction induces premature synapse maturation and enhanced synaptogenesis in the dorsal hippocampus, alongside deficits in NMDAR-dependent LTD. Proteomic analyses uncovered dysregulation of signaling, ion homeostasis, ubiquitination, translation, oxidative stress, and neuroinflammation pathways. These findings suggest that Mdga2 loss disrupts early synaptic development and circuit refinement, contributing to autism-like phenotypes and persistent alterations in synaptic signaling.