ArticlePLoS biology2025
Mdga2 deficiency leads to an aberrant activation of BDNF/TrkB signaling that underlies autism-relevant synaptic and behavioral changes in mice.
Article in PLoS biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- The genetic architecture of fibromyalgia across 2.5 million individuals.Nature medicine · 2026Article
- Genomic Copy Number Variants Associated With Strabismus and Amblyopia in the All of Us Research Program.Investigative ophthalmology & visual science · 2026Article
- MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy.American journal of human genetics · 2026Article
- Sex-dimorphic reprogramming of fetal mouse brain development by maternal estradiol excess.Biology of sex differences · 2025Article
- The genetic architecture of fibromyalgia across 2.5 million individuals.medRxiv : the preprint server for health sciences · 2025Article
- Ketone body β-hydroxybutyrate-mediated histone β-hydroxybutyrylation upregulates lipolysis and attenuates metabolic syndrome.American journal of physiology. Cell physiology · 2025Article
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Authors and funding
10 authors.
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Abstract
Memprin/A5/mu (MAM) domain containing glycosylphosphatidylinositol anchor 2 (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 brain-derived neurotrophic factor/tyrosine kinase B (BDNF/TrkB) signaling activation in these mice. We demonstrate that MDGA2 interacts with TrkB through its memprin/A5/mu 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 α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (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.
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