Postsynaptic receptors regulate presynaptic transmitter stability through transsynaptic bridges

• 成果类型: Article
• 署名作者: Godavarthi, Swetha K.; Hiramoto, Masaki; Ignatyev, Yuri; Levin, Jacqueline B.; Li, Hui-quan; Pratelli, Marta; Borchardt, Jennifer; Czajkowski, Cynthia; Borodinsky, Laura N.; Sweeney, Lora; Cline, Hollis T.; Spitzer, Nicholas C.
• 署名单位: University of California System; University of California San Diego; University of California System; University of California San Diego; Scripps Research Institute; Institute of Science & Technology - Austria; University of California System; University of California Davis; University of Wisconsin System; University of Wisconsin Madison
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11878
• DOI: 10.1073/pnas.2318041121
• 发表日期: 2024-04-09
• 关键词: developing neuromuscular synapses; synaptic vesicles; neurotransmitter release; acetylcholine-receptor; asynchronous release; snare complex; ca2+ sensor; synaptotagmin isoforms; molecular-mechanisms; electrical-activity

摘要

Stable matching of neurotransmitters with their receptors is fundamental to synapse function and reliable communication in neural circuits. Presynaptic neurotransmitters regulate the stabilization of postsynaptic transmitter receptors. Whether postsynaptic receptors regulate stabilization of presynaptic transmitters has received less attention. Here, we show that blockade of endogenous postsynaptic acetylcholine receptors (AChR) at the neuromuscular junction destabilizes the cholinergic phenotype in motor neurons and stabilizes an earlier, developmentally transient glutamatergic phenotype. Further, expression of exogenous postsynaptic gamma- aminobutyric acid type A receptors (GABAA receptors) in muscle cells stabilizes an earlier, developmentally transient GABAergic motor neuron phenotype. Both AChR and GABAA receptors are linked to presynaptic neurons through transsynaptic bridges. Knockdown of specific components of these transsynaptic bridges prevents stabilization of the cholinergic or GABAergic phenotypes. Bidirectional communication can enforce a match between transmitter and receptor and ensure the fidelity of synaptic transmission. Our findings suggest a potential role of dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter.