MDGAs perform activity- dependent synapse type- specific suppression via distinct extracellular mechanisms

• 成果类型: Article
• 署名作者: Kim, Seungjoon; Jang, Gyubin; Kim, Hyeonho; Lim, Dongseok; Han, Kyung Ah; Um, Ji Won; Ko, Jaewon
• 署名单位: Daegu Gyeongbuk Institute of Science & Technology (DGIST); Daegu Gyeongbuk Institute of Science & Technology (DGIST)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-15153
• DOI: 10.1073/pnas.2322978121
• 发表日期: 2024-06-25
• 关键词: nmda receptors; neuroligin-1; adhesion; transmission; inhibition; modulation; diversity; neurexins

摘要

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 alpha- 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.