Bazedoxifene reverses sexually dimorphic autistic-like abnormalities in biallelic MDGA1-mutant mice

MDGA1 reportedly suppresses GABAergic synaptic inhibition and may be associated with schizophrenia. However, it has been unclear whether and how MDGA1 dysfunction causes neurodevelopmental disorders. Here, we describe two patients with autism spectrum disorder (ASD) carrying missense mutations in MDGA1: p.Val116Met/p.Ala688Val and p.Tyr635Cys/p.Glu756Gln. Murine in utero overexpression of MDGA1 p.Val116Met/p.Ala688Val alters normal cortical neuron migration and impairs ultrasonic vocalizations (USVs). The p.Tyr635Cys/p.Glu756Gln substitution disrupts the triangular extracellular structure of MDGA1 and renders it unable to impact GABAergic synapses in hippocampal CA1 neurons. Male Mdga1 knock-in (KI) mouse pups and adults harboring the p.Tyr636Cys/p.Glu751Gln mutation exhibit impaired USVs and sensorimotor gating, similar to male Mdga1 conditional knockout (cKO) mice. No behavioral deficits were seen in female counterparts. Bazedoxifene (a selective estrogen receptor modulator) treatment of male Mdga1^Y636C/E751Q KI mice rescues the changes in the expression and phosphorylation of a subset of GABAergic synaptic proteins, as well as behavioral performance and GABAergic synaptic strength. Thus, different MDGA1 mutations manifest as distinct MDGA1 dysfunctions and are likely to cause ASD via sexually dimorphic loss-of-function and/or gain-of-function mechanisms.