MDGA2 constrains the BDNF/TrkB signaling

MDGA2 is an excitatory synaptic suppressor and its mutations have been associated with autism spectrum disorder (ASD). However, the detailed physiological function of MDGA2 and the mechanism underlying MDGA2 deficiency-caused ASD has yet to be elucidated. Herein, we not only confirm that Mdga2+/- mice exhibit increased excitatory synapse transmission and ASD-like behaviors, but also identify aberrant BDNF/TrkB signaling activation in these mice. We demonstrate that MDGA2 interacts with TrkB through its MAM domain, thereby competing the binding of BDNF to TrkB. Both loss of MDGA2 and the ASD-associated MDGA2 V930I mutation promote the BDNF/TrkB signaling activity. Importantly, we demonstrate that inhibiting the BDNF/TrkB signaling by both small molecular compound and MDGA2-derived peptide can attenuate the increase of AMPA receptor-mediated excitatory synaptic activity and social deficits in MDGA2 deficient mice. These results highlight a novel MDGA2-BDNF/TrkB-dependent mechanism underlying the synaptic function regulation, which may become a therapeutic target for ASD.