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Proc. Natl. Acad. Sci. USA, June 20, 2024, 121 (26) | https://doi.org/10.1073/pnas.2322978121 MDGAs perform activity-dependent synapse type-specific suppression via distinct extracellular mechanisms

Seungjoon Kim^a,b,1, Gyubin Jang^a,b,1, Hyeonho Kim^a,b, Dongseok Lim^a, Kyung Ah Han^a,b, Ji Won Um^a,b, and Jaewon Ko^a,b,2

^aDepartment of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Korea; and

^bCenter for Synapse Diversity and Specificity, Daegu Gyeongbuk Institute of Science and Technology, Daegu 42988, Korea

¹S.K. and G.J. contributed equally to this work.

²To whom correspondence may be addressed. : Jaewon Ko

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.

논문정보

형식Research article
게재일2024년 06월 (BRIC 등록일 2024-06-23)
연구진국내 연구진
분야 생명과학 > 신경생물학

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