biostudies-literatureKim SNational Research Foundation of Korea (NRF)Daegu Gyeongbuk Institute of Science and TechnologyDaegu Gyeongbuk Institute of Science and Technology (DGIST)National Research Foundation of Koreae2322978121https://www.ebi.ac.uk/biostudies/studies/S-EPMC11214077biostudies-literatureUnknown121(26)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 thProceedings of the National Academy of Sciences of the United States of AmericaMDGAs perform activity-dependent synapse type-specific suppression via distinct extracellular mechanisms.PMC112140772022R1A3B107720623-CoE-BT-012022R1C1C2003499Kim SLim DKim HJang GHan KAUm JWKo JfalseMDGAs perform activity-dependent synapse type-specific suppression via distinct extracellular mechanisms.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 th2024-01-01T00:00:00Z2024 Jun2026-06-03T00:47:43.364Z2025-04-04T00:38:35.697ZS-EPMC112140773890079110.1073/pnas.2322978121