GABAB receptors induce phasic release from medial habenula terminals through activity- dependent recruitment of release- ready vesicles

• 成果类型: Article
• 署名作者: Koppensteiner, Peter; Bhandari, Pradeep; Oenal, Cihan; Merjane, Carolina Borges-; Le Monnier, Elodie; Roy, Utsa; Nakamura, Yukihiro; Sadakata, Tetsushi; Sanbo, Makoto; Hirabayashi, Masumi; Rhee, Jeongseop; Brose, Nils; Jonas, Peter; Shigemoto, Ryuichi
• 署名单位: University of Basel; Institute of Science & Technology - Austria; Jikei University; Gunma University; National Institutes of Natural Sciences (NINS) - Japan; National Institute for Physiological Sciences (NIPS)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10950
• DOI: 10.1073/pnas.2301449121
• 发表日期: 2024-02-20
• 关键词: ca2+-dependent activator protein; pool; secretion; neurons; caps2; rat; synaptoporin; modulation; inhibition; channels

摘要

GABAB receptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust poten-tiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation on MHb terminals induces an activity- dependent transition from a facilitating, tonic to a depressing, phasic neurotransmitter release mode. This transition is accompanied by a 4.1- fold increase in readily releasable vesicle pool (RRP) size and a 3.5- fold increase of docked synaptic vesicles (SVs) at the presyn-aptic active zone (AZ). Strikingly, the depressing phasic release exhibits looser coupling distance than the tonic release. Furthermore, the tonic and phasic release are selectively affected by deletion of synaptoporin (SPO) and Ca2+- dependent activator protein for secretion 2 (CAPS2), respectively. SPO modulates augmentation, the short- term plas-ticity associated with tonic release, and CAPS2 retains the increased RRP for initial responses in phasic response trains. The cytosolic protein CAPS2 showed a SV- associated distribution similar to the vesicular transmembrane protein SPO, and they were colo-calized in the same terminals. We developed the Flash and Freeze- fracture method, and revealed the release of SPO- associated vesicles in both tonic and phasic modes and activity- dependent recruitment of CAPS2 to the AZ during phasic release, which lasted several minutes. Overall, these results indicate that GBR activation translocates CAPS2 to the AZ along with the fusion of CAPS2- associated SVs, contributing to persistency of the RRP increase. Thus, we identified structural and molecular mechanisms under-lying tonic and phasic neurotransmitter release and their transition by GBR activation in MHb terminals.