---
APC_amount: 5887,8 EUR
OA_place: publisher
OA_type: hybrid
_id: '15084'
abstract:
- lang: eng
  text: "GABAB receptor (GBR) activation inhibits neurotransmitter release in axon
    terminals in the brain, except in medial habenula (MHb) terminals, which show
    robust potentiation. 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 presynaptic 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 Ca\r\n            <jats:sup>2+</jats:sup>\r\n            -dependent
    activator protein for secretion 2 (CAPS2), respectively. SPO modulates augmentation,
    the short-term plasticity 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 colocalized 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 underlying tonic
    and phasic neurotransmitter release and their transition by GBR activation in
    MHb terminals."
acknowledged_ssus:
- _id: M-Shop
- _id: PreCl
- _id: EM-Fac
acknowledgement: We thank Erwin Neher and Ipe Ninan for critical comments on the manuscript.
  This project has received funding from the European Research Council (ERC) and European
  Commission, under the European Union’s Horizon 2020 research and innovation program
  (ERC grant agreement no. 694539 to R.S. and the Marie Skłodowska-Curie grant agreement
  no. 665385 to C.Ö.). This study was supported by the Cooperative Study Program of
  Center for Animal Resources and Collaborative Study of NINS. We thank Kohgaku Eguchi
  for statistical analysis, Yu Kasugai for additional EM imaging, Robert Beattie for
  the design of the slice recovery chamber for Flash and Freeze experiments, Todor
  Asenov from the ISTA machine shop for custom part preparations for high-pressure
  freezing, the ISTA preclinical facility for animal caretaking, and the ISTA EM facilities
  for technical support.
article_number: e2301449121
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Peter
  full_name: Koppensteiner, Peter
  id: 3B8B25A8-F248-11E8-B48F-1D18A9856A87
  last_name: Koppensteiner
  orcid: 0000-0002-3509-1948
- first_name: Pradeep
  full_name: Bhandari, Pradeep
  id: 45EDD1BC-F248-11E8-B48F-1D18A9856A87
  last_name: Bhandari
  orcid: 0000-0003-0863-4481
- first_name: Hüseyin C
  full_name: Önal, Hüseyin C
  id: 4659D740-F248-11E8-B48F-1D18A9856A87
  last_name: Önal
  orcid: 0000-0002-2771-2011
- first_name: Carolina
  full_name: Borges Merjane, Carolina
  id: 4305C450-F248-11E8-B48F-1D18A9856A87
  last_name: Borges Merjane
  orcid: 0000-0003-0005-401X
- first_name: Elodie
  full_name: Le Monnier, Elodie
  id: 3B59276A-F248-11E8-B48F-1D18A9856A87
  last_name: Le Monnier
- first_name: Utsa
  full_name: Roy, Utsa
  id: 4d26cf11-5355-11ee-ae5a-eb05e255b9b2
  last_name: Roy
- first_name: Yukihiro
  full_name: Nakamura, Yukihiro
  last_name: Nakamura
- first_name: Tetsushi
  full_name: Sadakata, Tetsushi
  last_name: Sadakata
- first_name: Makoto
  full_name: Sanbo, Makoto
  last_name: Sanbo
- first_name: Masumi
  full_name: Hirabayashi, Masumi
  last_name: Hirabayashi
- first_name: JeongSeop
  full_name: Rhee, JeongSeop
  last_name: Rhee
- first_name: Nils
  full_name: Brose, Nils
  last_name: Brose
- first_name: Peter M
  full_name: Jonas, Peter M
  id: 353C1B58-F248-11E8-B48F-1D18A9856A87
  last_name: Jonas
  orcid: 0000-0001-5001-4804
- first_name: Ryuichi
  full_name: Shigemoto, Ryuichi
  id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
  last_name: Shigemoto
  orcid: 0000-0001-8761-9444
citation:
  ama: Koppensteiner P, Bhandari P, Önal C, et al. GABAB receptors induce phasic release
    from medial habenula terminals through activity-dependent recruitment of release-ready
    vesicles. <i>Proceedings of the National Academy of Sciences of the United States
    of America</i>. 2024;121(8). doi:<a href="https://doi.org/10.1073/pnas.2301449121">10.1073/pnas.2301449121</a>
  apa: Koppensteiner, P., Bhandari, P., Önal, C., Borges Merjane, C., Le Monnier,
    E., Roy, U., … Shigemoto, R. (2024). GABAB receptors induce phasic release from
    medial habenula terminals through activity-dependent recruitment of release-ready
    vesicles. <i>Proceedings of the National Academy of Sciences of the United States
    of America</i>. National Academy of Sciences. <a href="https://doi.org/10.1073/pnas.2301449121">https://doi.org/10.1073/pnas.2301449121</a>
  chicago: Koppensteiner, Peter, Pradeep Bhandari, Cihan Önal, Carolina Borges Merjane,
    Elodie Le Monnier, Utsa Roy, Yukihiro Nakamura, et al. “GABAB Receptors Induce
    Phasic Release from Medial Habenula Terminals through Activity-Dependent Recruitment
    of Release-Ready Vesicles.” <i>Proceedings of the National Academy of Sciences
    of the United States of America</i>. National Academy of Sciences, 2024. <a href="https://doi.org/10.1073/pnas.2301449121">https://doi.org/10.1073/pnas.2301449121</a>.
  ieee: P. Koppensteiner <i>et al.</i>, “GABAB receptors induce phasic release from
    medial habenula terminals through activity-dependent recruitment of release-ready
    vesicles,” <i>Proceedings of the National Academy of Sciences of the United States
    of America</i>, vol. 121, no. 8. National Academy of Sciences, 2024.
  ista: Koppensteiner P, Bhandari P, Önal C, Borges Merjane C, Le Monnier E, Roy U,
    Nakamura Y, Sadakata T, Sanbo M, Hirabayashi M, Rhee J, Brose N, Jonas PM, Shigemoto
    R. 2024. GABAB receptors induce phasic release from medial habenula terminals
    through activity-dependent recruitment of release-ready vesicles. Proceedings
    of the National Academy of Sciences of the United States of America. 121(8), e2301449121.
  mla: Koppensteiner, Peter, et al. “GABAB Receptors Induce Phasic Release from Medial
    Habenula Terminals through Activity-Dependent Recruitment of Release-Ready Vesicles.”
    <i>Proceedings of the National Academy of Sciences of the United States of America</i>,
    vol. 121, no. 8, e2301449121, National Academy of Sciences, 2024, doi:<a href="https://doi.org/10.1073/pnas.2301449121">10.1073/pnas.2301449121</a>.
  short: P. Koppensteiner, P. Bhandari, C. Önal, C. Borges Merjane, E. Le Monnier,
    U. Roy, Y. Nakamura, T. Sadakata, M. Sanbo, M. Hirabayashi, J. Rhee, N. Brose,
    P.M. Jonas, R. Shigemoto, Proceedings of the National Academy of Sciences of the
    United States of America 121 (2024).
corr_author: '1'
date_created: 2024-03-05T09:23:55Z
date_published: 2024-02-20T00:00:00Z
date_updated: 2026-07-14T22:30:24Z
day: '20'
ddc:
- '570'
department:
- _id: RySh
- _id: PeJo
doi: 10.1073/pnas.2301449121
ec_funded: 1
external_id:
  isi:
  - '001208567300006'
  pmid:
  - '38346189'
file:
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has_accepted_license: '1'
intvolume: '       121'
isi: 1
issue: '8'
language:
- iso: eng
month: '02'
oa: 1
oa_version: Published Version
pmid: 1
project:
- _id: 25CA28EA-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '694539'
  name: 'In situ analysis of single channel subunit composition in neurons: physiological
    implication in synaptic plasticity and behaviour'
- _id: 2564DBCA-B435-11E9-9278-68D0E5697425
  call_identifier: H2020
  grant_number: '665385'
  name: International IST Doctoral Program
publication: Proceedings of the National Academy of Sciences of the United States
  of America
publication_identifier:
  eissn:
  - 1091-6490
  issn:
  - 0027-8424
publication_status: published
publisher: National Academy of Sciences
quality_controlled: '1'
related_material:
  link:
  - description: News on ISTA Website
    relation: press_release
    url: https://ista.ac.at/en/news/neuronal-insights-flash-and-freeze-fracture/
  record:
  - id: '13173'
    relation: research_data
    status: public
  - id: '19271'
    relation: dissertation_contains
    status: public
scopus_import: '1'
status: public
title: GABAB receptors induce phasic release from medial habenula terminals through
  activity-dependent recruitment of release-ready vesicles
tmp:
  image: /images/cc_by_nc_nd.png
  legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
  name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
    (CC BY-NC-ND 4.0)
  short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 317138e5-6ab7-11ef-aa6d-ffef3953e345
volume: 121
year: '2024'
...