MDGA1 negatively regulates amyloid precursor protein-mediated synapse inhibition in the hippocampus.
MDGA1 negatively regulates amyloid precursor protein-mediated synapse inhibition in the hippocampus.
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DOI：
10.1073/pnas.2115326119
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发表时间：
2022-01-25
影响因子：
11.1
通讯作者：
Ko J
中科院分区：
文献类型：
--
作者：
Kim J;Kim S;Kim H;Hwang IW;Bae S;Karki S;Kim D;Ogelman R;Bang G;Kim JY;Kajander T;Um JW;Oh WC;Ko J
这项研究表明，一个普遍的突触机制负责调整GABA能神经回路的强度和营业额。这些观察结果与神经回路动力学的问题有关，神经回路动力学仅在某些有限的背景下进行了研究，特别是在一个子集的神经元回路中。我们的工作提供了令人信服的证据，支持淀粉样前体蛋白（APP）在塑造GABA能神经回路中的关键和独特的生理作用。我们明确的MDGA 1-APP复合物在特定的海马GABA能神经回路的生理意义的证明，使我们能够提出一个概念框架，除了揭示APP蛋白以前未确定的生理作用外，还为我们对哺乳动物抑制性突触组织的理解增加了一个惊人的转折。由多种突触粘附蛋白控制的平衡的突触抑制对于适当的脑功能至关重要。MDGA 1（meprin，A-5蛋白和受体蛋白-酪氨酸磷酸酶mu [MAM]结构域含糖基磷脂酰肌醇锚蛋白1）抑制哺乳动物神经元中的突触抑制，但MDGA 1介导的GABA能突触负调节的分子机制尚未解决。在这里，我们表明，MDGA 1 MAM结构域直接与淀粉样前体蛋白（APP）的延伸结构域相互作用。引人注目的是，MDGA 1介导的突触去抑制需要MDGA 1 MAM结构域，并且在海马CA 1锥体神经元的远端树突处突出。突触前GABA能中间神经元中APP的下调特异性地抑制GABA能，但不抑制海马CA 1锥体神经元的体细胞和树突隔室的GABA能突触传递强度和输入。此外，APP删除表现出不同的影响，生长抑素和小清蛋白阳性的中间神经元在海马CA 1区，导致抑制性突触数量，传输和兴奋性的明显改变。输注MDGA 1 MAM蛋白模拟突触后MDGA 1功能获得表型，涉及突触前APP.MDGA1野生型或MAM的过度表达，但不是MAM缺失的MDGA 1，在海马CA 1损害小鼠的新物体识别记忆。因此，我们的研究结果确立了APP-MDGA 1复合物在海马神经回路中的独特作用，为神经元隔室特异性突触抑制的差异调节的跨突触机制提供了前所未有的见解。
This study demonstrates a universal synaptic mechanism responsible for tuning GABAergic neural circuit strength and turnover. These observations are relevant to the issue of neural circuit dynamics, which have only been investigated in certain limited contexts, particularly at a subset of glutamatergic neural circuits. Our work provides compelling evidence to support a crucial and unique physiological role for amyloid precursor protein (APP) in shaping GABAergic neural circuits. Our unequivocal demonstration of the physiological significance of MDGA1–APP complexes at specific hippocampal GABAergic neural circuits enables us to propose a conceptual framework that adds a striking twist to our understanding of the organization of mammalian inhibitory synapses in addition to unmasking a previously unidentified physiological role for APP proteins. Balanced synaptic inhibition, controlled by multiple synaptic adhesion proteins, is critical for proper brain function. MDGA1 (meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu [MAM] domain-containing glycosylphosphatidylinositol anchor protein 1) suppresses synaptic inhibition in mammalian neurons, yet the molecular mechanisms underlying MDGA1-mediated negative regulation of GABAergic synapses remain unresolved. Here, we show that the MDGA1 MAM domain directly interacts with the extension domain of amyloid precursor protein (APP). Strikingly, MDGA1-mediated synaptic disinhibition requires the MDGA1 MAM domain and is prominent at distal dendrites of hippocampal CA1 pyramidal neurons. Down-regulation of APP in presynaptic GABAergic interneurons specifically suppressed GABAergic, but not glutamatergic, synaptic transmission strength and inputs onto both the somatic and dendritic compartments of hippocampal CA1 pyramidal neurons. Moreover, APP deletion manifested differential effects in somatostatin- and parvalbumin-positive interneurons in the hippocampal CA1, resulting in distinct alterations in inhibitory synapse numbers, transmission, and excitability. The infusion of MDGA1 MAM protein mimicked postsynaptic MDGA1 gain-of-function phenotypes that involve the presence of presynaptic APP. The overexpression of MDGA1 wild type or MAM, but not MAM-deleted MDGA1, in the hippocampal CA1 impaired novel object-recognition memory in mice. Thus, our results establish unique roles of APP–MDGA1 complexes in hippocampal neural circuits, providing unprecedented insight into trans-synaptic mechanisms underlying differential tuning of neuronal compartment-specific synaptic inhibition.
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影响因子：
64.5
作者：
Loh, Ken H.;Stawski, Philipp S.;Draycott, Austin S.;Udeshi, Namrata D.;Lehrman, Emily K.;Wilton, Daniel K.;Svinkina, Tanya;Deerinck, Thomas J.;Ellisman, Mark H.;Stevens, Beth;Carr, Steven A.;Ting, Alice Y.
通讯作者：
Ting, Alice Y.
影响因子：
16.2
作者：
Elegheert J;Cvetkovska V;Clayton AJ;Heroven C;Vennekens KM;Smukowski SN;Regan MC;Jia W;Smith AC;Furukawa H;Savas JN;de Wit J;Begbie J;Craig AM;Aricescu AR
通讯作者：
Aricescu AR
影响因子：
16.2
作者：
Lee SH;Kang J;Ho A;Watanabe H;Bolshakov VY;Shen J
通讯作者：
Shen J
影响因子：
16.6
作者：
Dinamarca, Margarita C.;Raveh, Adi;Bettler, Bernhard
通讯作者：
Bettler, Bernhard
影响因子：
5.4
作者：
Mueller, Ulrike C.;Zheng, Hui
通讯作者：
Zheng, Hui