Bazedoxifene reverses sexually dimorphic autistic-like abnormalities in biallelic MDGA1-mutant mice - PubMed
5 hours ago
- #Autism Spectrum Disorder
- #GABAergic Synapse
- #MDGA1
- Two patients with autism spectrum disorder (ASD) carried missense mutations in MDGA1: p.Val116Met/p.Ala688Val and p.Tyr635Cys/p.Glu756Gln.
- Murine in utero overexpression of MDGA1 p.Val116Met/p.Ala688Val altered cortical neuron migration and impaired ultrasonic vocalizations (USVs).
- The p.Tyr635Cys/p.Glu756Gln substitution disrupted the extracellular structure of MDGA1, affecting GABAergic synapses in hippocampal CA1 neurons.
- Male Mdga1 knock-in (KI) mice with p.Tyr636Cys/p.Glu751Gln mutation showed impaired USVs and sensorimotor gating, similar to male Mdga1 conditional knockout (cKO) mice.
- Female counterparts exhibited no behavioral deficits.
- Bazedoxifene treatment rescued GABAergic synaptic protein expression, phosphorylation, behavioral performance, and synaptic strength in male Mdga1Y636C/E751Q KI mice.
- MDGA1 mutations likely cause ASD via sexually dimorphic loss-of-function and/or gain-of-function mechanisms.