ArticleProceedings of the National Academy of Sciences of the United States of America2024
MDGAs perform activity-dependent synapse type-specific suppression via distinct extracellular mechanisms.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Neurexins, Ephrin receptors, and N-cadherin signaling as emerging mechanisms in synaptic dysfunction and neurodegenerative diseases.Communications biology · 2026Review
- Bazedoxifene reverses sexually dimorphic autistic-like abnormalities in biallelic MDGA1-mutant mice.EMBO molecular medicine · 2026Article
- Localization and Functional Characterization of MDGA1 in Mouse Hippocampus.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- MDGA2 homozygous loss-of-function variants cause developmental and epileptic encephalopathy.American journal of human genetics · 2026Article
- CASKIN2 mediates PTPσ-orchestrated transsynaptic mechanisms at excitatory synapses.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- High-content image-based pooled screens reveal regulators of synaptogenesis.Cell reports · 2025Article
- EphB2 receptor tyrosine kinase-mediated excitatory synaptic functions are negatively modulated by MDGA2.Progress in neurobiology · 2025Article
- Mdga2 deficiency leads to an aberrant activation of BDNF/TrkB signaling that underlies autism-relevant synaptic and behavioral changes in mice.PLoS biology · 2025Article
- Chronic stress induces depression through MDGA1-Neuroligin2 mediated suppression of inhibitory synapses in the lateral habenula.Theranostics · 2025Article
- RPS23RG1 inhibits SORT1-mediated lysosomal degradation of MDGA2 to protect against autism.Theranostics · 2025Article
- Functional Neuroligin-2-MDGA1 interactions differentially regulate synaptic GABACommunications biology · 2024Article
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Authors and funding
7 authors.
Funding
Abstract
MDGA (MAM domain containing glycosylphosphatidylinositol anchor) family proteins were previously identified as synaptic suppressive factors. However, various genetic manipulations have yielded often irreconcilable results, precluding precise evaluation of MDGA functions. Here, we found that, in cultured hippocampal neurons, conditional deletion of MDGA1 and MDGA2 causes specific alterations in synapse numbers, basal synaptic transmission, and synaptic strength at GABAergic and glutamatergic synapses, respectively. Moreover, MDGA2 deletion enhanced both N-methyl-D-aspartate (NMDA) receptor- and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated postsynaptic responses. Strikingly, ablation of both MDGA1 and MDGA2 abolished the effect of deleting individual MDGAs that is abrogated by chronic blockade of synaptic activity. Molecular replacement experiments further showed that MDGA1 requires the meprin/A5 protein/PTPmu (MAM) domain, whereas MDGA2 acts via neuroligin-dependent and/or MAM domain-dependent pathways to regulate distinct postsynaptic properties. Together, our data demonstrate that MDGA paralogs act as unique negative regulators of activity-dependent postsynaptic organization at distinct synapse types, and cooperatively contribute to adjustment of excitation-inhibition balance.
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