---
_id: '12875'
abstract:
- lang: eng
text: The superior colliculus (SC) in the mammalian midbrain is essential for multisensory
integration and is composed of a rich diversity of excitatory and inhibitory neurons
and glia. However, the developmental principles directing the generation of SC
cell-type diversity are not understood. Here, we pursued systematic cell lineage
tracing in silico and in vivo, preserving full spatial information, using genetic
mosaic analysis with double markers (MADM)-based clonal analysis with single-cell
sequencing (MADM-CloneSeq). The analysis of clonally related cell lineages revealed
that radial glial progenitors (RGPs) in SC are exceptionally multipotent. Individual
resident RGPs have the capacity to produce all excitatory and inhibitory SC neuron
types, even at the stage of terminal division. While individual clonal units show
no pre-defined cellular composition, the establishment of appropriate relative
proportions of distinct neuronal types occurs in a PTEN-dependent manner. Collectively,
our findings provide an inaugural framework at the single-RGP/-cell level of the
mammalian SC ontogeny.
acknowledged_ssus:
- _id: Bio
- _id: M-Shop
- _id: LifeSc
- _id: PreCl
acknowledgement: "We thank Liqun Luo for his continued support, for providing essential
resources for generating Fzd10-CreER mice which were generated in his laboratory,
and for comments on the manuscript; W. Zhong for providing Nestin-Cre transgenic
mouse line for this study; A. Heger for mouse colony management; R. Beattie and
T. Asenov for designing and producing components of acute slice recovery chamber
for MADM-CloneSeq experiments; and K. Leopold, J. Rodarte and N. Amberg for initial
experiments, technical support and/or assistance. This study was supported by the
Scientific Service Units (SSU) of IST Austria through resources provided by the
Imaging & Optics Facility (IOF), Laboratory Support Facility (LSF), Miba Machine
Shop, and Pre-clinical Facility (PCF). G.C. received funding from European Commission
(IST plus postdoctoral fellowship). This work was supported by ISTA institutional\r\nfunds;
the Austrian Science Fund Special Research Programmes (FWF SFB F78 Neuro Stem Modulation)
to S.H. "
article_processing_charge: Yes (via OA deal)
article_type: original
author:
- first_name: Giselle T
full_name: Cheung, Giselle T
id: 471195F6-F248-11E8-B48F-1D18A9856A87
last_name: Cheung
orcid: 0000-0001-8457-2572
- first_name: Florian
full_name: Pauler, Florian
id: 48EA0138-F248-11E8-B48F-1D18A9856A87
last_name: Pauler
orcid: 0000-0002-7462-0048
- first_name: Peter
full_name: Koppensteiner, Peter
id: 3B8B25A8-F248-11E8-B48F-1D18A9856A87
last_name: Koppensteiner
orcid: 0000-0002-3509-1948
- first_name: Thomas
full_name: Krausgruber, Thomas
last_name: Krausgruber
- first_name: Carmen
full_name: Streicher, Carmen
id: 36BCB99C-F248-11E8-B48F-1D18A9856A87
last_name: Streicher
- first_name: Martin
full_name: Schrammel, Martin
id: f13e7cae-e8bd-11ed-841a-96dedf69f46d
last_name: Schrammel
- first_name: Natalie Y
full_name: Özgen, Natalie Y
id: e68ece33-f6e0-11ea-865d-ae1031dcc090
last_name: Özgen
- first_name: Alexis
full_name: Ivec, Alexis
id: 1d144691-e8be-11ed-9b33-bdd3077fad4c
last_name: Ivec
- first_name: Christoph
full_name: Bock, Christoph
last_name: Bock
- first_name: Ryuichi
full_name: Shigemoto, Ryuichi
id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
last_name: Shigemoto
orcid: 0000-0001-8761-9444
- first_name: Simon
full_name: Hippenmeyer, Simon
id: 37B36620-F248-11E8-B48F-1D18A9856A87
last_name: Hippenmeyer
orcid: 0000-0003-2279-1061
citation:
ama: Cheung GT, Pauler F, Koppensteiner P, et al. Multipotent progenitors instruct
ontogeny of the superior colliculus. Neuron. 2024;112(2):230-246.e11. doi:10.1016/j.neuron.2023.11.009
apa: Cheung, G. T., Pauler, F., Koppensteiner, P., Krausgruber, T., Streicher, C.,
Schrammel, M., … Hippenmeyer, S. (2024). Multipotent progenitors instruct ontogeny
of the superior colliculus. Neuron. Elsevier. https://doi.org/10.1016/j.neuron.2023.11.009
chicago: Cheung, Giselle T, Florian Pauler, Peter Koppensteiner, Thomas Krausgruber,
Carmen Streicher, Martin Schrammel, Natalie Y Özgen, et al. “Multipotent Progenitors
Instruct Ontogeny of the Superior Colliculus.” Neuron. Elsevier, 2024.
https://doi.org/10.1016/j.neuron.2023.11.009.
ieee: G. T. Cheung et al., “Multipotent progenitors instruct ontogeny of
the superior colliculus,” Neuron, vol. 112, no. 2. Elsevier, p. 230–246.e11,
2024.
ista: Cheung GT, Pauler F, Koppensteiner P, Krausgruber T, Streicher C, Schrammel
M, Özgen NY, Ivec A, Bock C, Shigemoto R, Hippenmeyer S. 2024. Multipotent progenitors
instruct ontogeny of the superior colliculus. Neuron. 112(2), 230–246.e11.
mla: Cheung, Giselle T., et al. “Multipotent Progenitors Instruct Ontogeny of the
Superior Colliculus.” Neuron, vol. 112, no. 2, Elsevier, 2024, p. 230–246.e11,
doi:10.1016/j.neuron.2023.11.009.
short: G.T. Cheung, F. Pauler, P. Koppensteiner, T. Krausgruber, C. Streicher, M.
Schrammel, N.Y. Özgen, A. Ivec, C. Bock, R. Shigemoto, S. Hippenmeyer, Neuron
112 (2024) 230–246.e11.
date_created: 2023-04-27T09:41:48Z
date_published: 2024-01-17T00:00:00Z
date_updated: 2024-03-05T09:43:02Z
day: '17'
ddc:
- '570'
department:
- _id: SiHi
- _id: RySh
doi: 10.1016/j.neuron.2023.11.009
external_id:
pmid:
- '38096816'
file:
- access_level: open_access
checksum: 32b3788f7085cf44a84108d8faaff3ce
content_type: application/pdf
creator: dernst
date_created: 2024-02-06T13:56:15Z
date_updated: 2024-02-06T13:56:15Z
file_id: '14944'
file_name: 2024_Neuron_Cheung.pdf
file_size: 5942467
relation: main_file
success: 1
file_date_updated: 2024-02-06T13:56:15Z
has_accepted_license: '1'
intvolume: ' 112'
issue: '2'
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '01'
oa: 1
oa_version: Published Version
page: 230-246.e11
pmid: 1
project:
- _id: 059F6AB4-7A3F-11EA-A408-12923DDC885E
grant_number: F07805
name: Molecular Mechanisms of Neural Stem Cell Lineage Progression
publication: Neuron
publication_identifier:
issn:
- 0896-6273
publication_status: published
publisher: Elsevier
quality_controlled: '1'
related_material:
link:
- description: News on ISTA Website
relation: press_release
url: https://ista.ac.at/en/news/the-pedigree-of-brain-cells/
scopus_import: '1'
status: public
title: Multipotent progenitors instruct ontogeny of the superior colliculus
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 112
year: '2024'
...
---
_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 2+\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. Proceedings of the National Academy of Sciences. 2024;121(8).
doi:10.1073/pnas.2301449121
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. Proceedings of the National Academy of Sciences. Proceedings
of the National Academy of Sciences. https://doi.org/10.1073/pnas.2301449121
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.” Proceedings of the National Academy of Sciences.
Proceedings of the National Academy of Sciences, 2024. https://doi.org/10.1073/pnas.2301449121.
ieee: P. Koppensteiner et al., “GABAB receptors induce phasic release from
medial habenula terminals through activity-dependent recruitment of release-ready
vesicles,” Proceedings of the National Academy of Sciences, vol. 121, no.
8. Proceedings of the 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. 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.”
Proceedings of the National Academy of Sciences, vol. 121, no. 8, e2301449121,
Proceedings of the National Academy of Sciences, 2024, doi:10.1073/pnas.2301449121.
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 121
(2024).
date_created: 2024-03-05T09:23:55Z
date_published: 2024-02-20T00:00:00Z
date_updated: 2024-03-12T13:44:18Z
day: '20'
ddc:
- '570'
department:
- _id: RySh
- _id: PeJo
doi: 10.1073/pnas.2301449121
ec_funded: 1
external_id:
pmid:
- '38346189'
file:
- access_level: open_access
checksum: b25b2a057c266ff317a48b0d54d6fc8a
content_type: application/pdf
creator: dernst
date_created: 2024-03-12T13:42:42Z
date_updated: 2024-03-12T13:42:42Z
file_id: '15110'
file_name: 2024_PNAS_Koppensteiner.pdf
file_size: 13648221
relation: main_file
success: 1
file_date_updated: 2024-03-12T13:42:42Z
has_accepted_license: '1'
intvolume: ' 121'
issue: '8'
language:
- iso: eng
license: https://creativecommons.org/licenses/by-nc-nd/4.0/
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
publication_identifier:
eissn:
- 1091-6490
issn:
- 0027-8424
publication_status: published
publisher: Proceedings of the 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
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: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 121
year: '2024'
...
---
_id: '14843'
abstract:
- lang: eng
text: The coupling between Ca2+ channels and release sensors is a key factor defining
the signaling properties of a synapse. However, the coupling nanotopography at
many synapses remains unknown, and it is unclear how it changes during development.
To address these questions, we examined coupling at the cerebellar inhibitory
basket cell (BC)-Purkinje cell (PC) synapse. Biophysical analysis of transmission
by paired recording and intracellular pipette perfusion revealed that the effects
of exogenous Ca2+ chelators decreased during development, despite constant reliance
of release on P/Q-type Ca2+ channels. Structural analysis by freeze-fracture replica
labeling (FRL) and transmission electron microscopy (EM) indicated that presynaptic
P/Q-type Ca2+ channels formed nanoclusters throughout development, whereas docked
vesicles were only clustered at later developmental stages. Modeling suggested
a developmental transformation from a more random to a more clustered coupling
nanotopography. Thus, presynaptic signaling developmentally approaches a point-to-point
configuration, optimizing speed, reliability, and energy efficiency of synaptic
transmission.
acknowledged_ssus:
- _id: EM-Fac
- _id: PreCl
- _id: M-Shop
acknowledgement: We thank Drs. David DiGregorio and Erwin Neher for critically reading
an earlier version of the manuscript, Ralf Schneggenburger for helpful discussions,
Benjamin Suter and Katharina Lichter for support with image analysis, Chris Wojtan
for advice on numerical solution of partial differential equations, Maria Reva for
help with Ripley analysis, Alois Schlögl for programming, and Akari Hagiwara and
Toshihisa Ohtsuka for anti-ELKS antibody. We are grateful to Florian Marr, Christina
Altmutter, and Vanessa Zheden for excellent technical assistance and to Eleftheria
Kralli-Beller for manuscript editing. This research was supported by the Scientific
Services Units (SSUs) of ISTA (Electron Microscopy Facility, Preclinical Facility,
and Machine Shop). The project received funding from the European Research Council
(ERC) under the European Union’s Horizon 2020 research and innovation program (grant
agreement no. 692692), the Fonds zur Förderung der Wissenschaftlichen Forschung
(Z 312-B27, Wittgenstein award; P 36232-B), all to P.J., and a DOC fellowship of
the Austrian Academy of Sciences to J.-J.C.
article_processing_charge: No
article_type: original
author:
- first_name: JingJing
full_name: Chen, JingJing
id: 2C4E65C8-F248-11E8-B48F-1D18A9856A87
last_name: Chen
- first_name: Walter
full_name: Kaufmann, Walter
id: 3F99E422-F248-11E8-B48F-1D18A9856A87
last_name: Kaufmann
orcid: 0000-0001-9735-5315
- first_name: Chong
full_name: Chen, Chong
id: 3DFD581A-F248-11E8-B48F-1D18A9856A87
last_name: Chen
- first_name: Itaru
full_name: Arai, Itaru
id: 32A73F6C-F248-11E8-B48F-1D18A9856A87
last_name: Arai
- first_name: Olena
full_name: Kim, Olena
id: 3F8ABDDA-F248-11E8-B48F-1D18A9856A87
last_name: Kim
- first_name: Ryuichi
full_name: Shigemoto, Ryuichi
id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
last_name: Shigemoto
orcid: 0000-0001-8761-9444
- first_name: Peter M
full_name: Jonas, Peter M
id: 353C1B58-F248-11E8-B48F-1D18A9856A87
last_name: Jonas
orcid: 0000-0001-5001-4804
citation:
ama: Chen J, Kaufmann W, Chen C, et al. Developmental transformation of Ca2+ channel-vesicle
nanotopography at a central GABAergic synapse. Neuron. doi:10.1016/j.neuron.2023.12.002
apa: Chen, J., Kaufmann, W., Chen, C., Arai, itaru, Kim, O., Shigemoto, R., &
Jonas, P. M. (n.d.). Developmental transformation of Ca2+ channel-vesicle nanotopography
at a central GABAergic synapse. Neuron. Elsevier. https://doi.org/10.1016/j.neuron.2023.12.002
chicago: Chen, JingJing, Walter Kaufmann, Chong Chen, itaru Arai, Olena Kim, Ryuichi
Shigemoto, and Peter M Jonas. “Developmental Transformation of Ca2+ Channel-Vesicle
Nanotopography at a Central GABAergic Synapse.” Neuron. Elsevier, n.d.
https://doi.org/10.1016/j.neuron.2023.12.002.
ieee: J. Chen et al., “Developmental transformation of Ca2+ channel-vesicle
nanotopography at a central GABAergic synapse,” Neuron. Elsevier.
ista: Chen J, Kaufmann W, Chen C, Arai itaru, Kim O, Shigemoto R, Jonas PM. Developmental
transformation of Ca2+ channel-vesicle nanotopography at a central GABAergic synapse.
Neuron.
mla: Chen, JingJing, et al. “Developmental Transformation of Ca2+ Channel-Vesicle
Nanotopography at a Central GABAergic Synapse.” Neuron, Elsevier, doi:10.1016/j.neuron.2023.12.002.
short: J. Chen, W. Kaufmann, C. Chen, itaru Arai, O. Kim, R. Shigemoto, P.M. Jonas,
Neuron (n.d.).
date_created: 2024-01-21T23:00:56Z
date_published: 2024-01-11T00:00:00Z
date_updated: 2024-03-14T13:14:18Z
day: '11'
department:
- _id: PeJo
- _id: EM-Fac
- _id: RySh
doi: 10.1016/j.neuron.2023.12.002
ec_funded: 1
external_id:
pmid:
- '38215739'
language:
- iso: eng
month: '01'
oa_version: None
pmid: 1
project:
- _id: 25B7EB9E-B435-11E9-9278-68D0E5697425
call_identifier: H2020
grant_number: '692692'
name: Biophysics and circuit function of a giant cortical glumatergic synapse
- _id: 25C5A090-B435-11E9-9278-68D0E5697425
call_identifier: FWF
grant_number: Z00312
name: The Wittgenstein Prize
- _id: bd88be38-d553-11ed-ba76-81d5a70a6ef5
grant_number: P36232
name: Mechanisms of GABA release in hippocampal circuits
- _id: 26B66A3E-B435-11E9-9278-68D0E5697425
grant_number: '25383'
name: Development of nanodomain coupling between Ca2+ channels and release sensors
at a central inhibitory synapse
publication: Neuron
publication_identifier:
eissn:
- 1097-4199
issn:
- 0896-6273
publication_status: inpress
publisher: Elsevier
quality_controlled: '1'
related_material:
link:
- description: News on ISTA Website
relation: press_release
url: https://ista.ac.at/en/news/synapses-brought-to-the-point/
record:
- id: '15101'
relation: dissertation_contains
status: public
scopus_import: '1'
status: public
title: Developmental transformation of Ca2+ channel-vesicle nanotopography at a central
GABAergic synapse
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
year: '2024'
...
---
_id: '12809'
abstract:
- lang: eng
text: "Understanding the mechanisms of learning and memory formation has always
been one of\r\nthe main goals in neuroscience. Already Pavlov (1927) in his early
days has used his classic\r\nconditioning experiments to study the neural mechanisms
governing behavioral adaptation.\r\nWhat was not known back then was that the
part of the brain that is largely responsible for\r\nthis type of associative
learning is the cerebellum.\r\nSince then, plenty of theories on cerebellar learning
have emerged. Despite their differences,\r\none thing they all have in common
is that learning relies on synaptic and intrinsic plasticity.\r\nThe goal of my
PhD project was to unravel the molecular mechanisms underlying synaptic\r\nplasticity
in two synapses that have been shown to be implicated in motor learning, in an\r\neffort
to understand how learning and memory formation are processed in the cerebellum.\r\nOne
of the earliest and most well-known cerebellar theories postulates that motor
learning\r\nlargely depends on long-term depression at the parallel fiber-Purkinje
cell (PC-PC) synapse.\r\nHowever, the discovery of other types of plasticity in
the cerebellar circuitry, like long-term\r\npotentiation (LTP) at the PC-PC synapse,
potentiation of molecular layer interneurons (MLIs),\r\nand plasticity transfer
from the cortex to the cerebellar/ vestibular nuclei has increased the\r\npopularity
of the idea that multiple sites of plasticity might be involved in learning.\r\nStill
a lot remains unknown about the molecular mechanisms responsible for these types
of\r\nplasticity and whether they occur during physiological learning.\r\nIn the
first part of this thesis we have analyzed the variation and nanodistribution
of voltagegated calcium channels (VGCCs) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid\r\ntype glutamate receptors (AMPARs) on the parallel fiber-Purkinje cell
synapse after vestibuloocular reflex phase reversal adaptation, a behavior that
has been suggested to rely on PF-PC\r\nLTP. We have found that on the last day
of adaptation there is no learning trace in form of\r\nVGCCs nor AMPARs variation
at the PF-PC synapse, but instead a decrease in the number of\r\nPF-PC synapses.
These data seem to support the view that learning is only stored in the\r\ncerebellar
cortex in an initial learning phase, being transferred later to the vestibular
nuclei.\r\nNext, we have studied the role of MLIs in motor learning using a relatively
simple and well characterized behavioral paradigm – horizontal optokinetic reflex
(HOKR) adaptation. We\r\nhave found behavior-induced MLI potentiation in form
of release probability increase that\r\ncould be explained by the increase of
VGCCs at the presynaptic side. Our results strengthen\r\nthe idea of distributed
cerebellar plasticity contributing to learning and provide a novel\r\nmechanism
for release probability increase. "
acknowledged_ssus:
- _id: EM-Fac
- _id: Bio
- _id: PreCl
alternative_title:
- ISTA Thesis
article_processing_charge: No
author:
- first_name: Catarina
full_name: Alcarva, Catarina
id: 3A96634C-F248-11E8-B48F-1D18A9856A87
last_name: Alcarva
citation:
ama: 'Alcarva C. Plasticity in the cerebellum: What molecular mechanisms are behind
physiological learning. 2023. doi:10.15479/at:ista:12809'
apa: 'Alcarva, C. (2023). Plasticity in the cerebellum: What molecular mechanisms
are behind physiological learning. Institute of Science and Technology Austria.
https://doi.org/10.15479/at:ista:12809'
chicago: 'Alcarva, Catarina. “Plasticity in the Cerebellum: What Molecular Mechanisms
Are behind Physiological Learning.” Institute of Science and Technology Austria,
2023. https://doi.org/10.15479/at:ista:12809.'
ieee: 'C. Alcarva, “Plasticity in the cerebellum: What molecular mechanisms are
behind physiological learning,” Institute of Science and Technology Austria, 2023.'
ista: 'Alcarva C. 2023. Plasticity in the cerebellum: What molecular mechanisms
are behind physiological learning. Institute of Science and Technology Austria.'
mla: 'Alcarva, Catarina. Plasticity in the Cerebellum: What Molecular Mechanisms
Are behind Physiological Learning. Institute of Science and Technology Austria,
2023, doi:10.15479/at:ista:12809.'
short: 'C. Alcarva, Plasticity in the Cerebellum: What Molecular Mechanisms Are
behind Physiological Learning, Institute of Science and Technology Austria, 2023.'
date_created: 2023-04-06T07:54:09Z
date_published: 2023-04-06T00:00:00Z
date_updated: 2023-04-26T12:16:56Z
day: '06'
ddc:
- '570'
degree_awarded: PhD
department:
- _id: GradSch
- _id: RySh
doi: 10.15479/at:ista:12809
file:
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checksum: 35b5997d2b0acb461f9d33d073da0df5
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creator: cchlebak
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date_updated: 2023-04-07T06:16:06Z
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file_size: 9881969
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creator: cchlebak
date_created: 2023-04-07T06:17:11Z
date_updated: 2023-04-07T06:17:11Z
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content_type: application/vnd.openxmlformats-officedocument.wordprocessingml.document
creator: cchlebak
date_created: 2023-04-07T06:18:05Z
date_updated: 2023-04-07T06:18:05Z
file_id: '12816'
file_name: Thesis_CatarinaAlcarva_final.docx
file_size: 84731244
relation: source_file
file_date_updated: 2023-04-07T06:18:05Z
has_accepted_license: '1'
language:
- iso: eng
month: '04'
oa_version: Published Version
page: '115'
project:
- _id: 267DFB90-B435-11E9-9278-68D0E5697425
name: 'Plasticity in the cerebellum: Which molecular mechanisms are behind physiological
learning?'
publication_identifier:
issn:
- 2663 - 337X
publication_status: published
publisher: Institute of Science and Technology Austria
status: public
supervisor:
- first_name: Ryuichi
full_name: Shigemoto, Ryuichi
id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
last_name: Shigemoto
orcid: 0000-0001-8761-9444
title: 'Plasticity in the cerebellum: What molecular mechanisms are behind physiological
learning'
type: dissertation
user_id: 8b945eb4-e2f2-11eb-945a-df72226e66a9
year: '2023'
...
---
_id: '14253'
abstract:
- lang: eng
text: Junctions between the endoplasmic reticulum (ER) and the plasma membrane (PM)
are specialized membrane contacts ubiquitous in eukaryotic cells. Concentration
of intracellular signaling machinery near ER-PM junctions allows these domains
to serve critical roles in lipid and Ca2+ signaling and homeostasis. Subcellular
compartmentalization of protein kinase A (PKA) signaling also regulates essential
cellular functions, however, no specific association between PKA and ER-PM junctional
domains is known. Here, we show that in brain neurons type I PKA is directed to
Kv2.1 channel-dependent ER-PM junctional domains via SPHKAP, a type I PKA-specific
anchoring protein. SPHKAP association with type I PKA regulatory subunit RI and
ER-resident VAP proteins results in the concentration of type I PKA between stacked
ER cisternae associated with ER-PM junctions. This ER-associated PKA signalosome
enables reciprocal regulation between PKA and Ca2+ signaling machinery to support
Ca2+ influx and excitation-transcription coupling. These data reveal that neuronal
ER-PM junctions support a receptor-independent form of PKA signaling driven by
membrane depolarization and intracellular Ca2+, allowing conversion of information
encoded in electrical signals into biochemical changes universally recognized
throughout the cell.
acknowledgement: We thank Kayla Templeton and Peter Turcanu for technical assistance,
Michelle Salemi for assistance with LC-MS data acquisition and analysis, Dr. Belvin
Gong for advice on monoclonal antibody generation, Drs. Maria Casas Prat and Eamonn
Dickson for assistance with super-resolution TIRF microscopy, Dr. Oscar Cerda for
assistance with the design of TAT-FFAT peptides, Dr. Fernando Santana for helpful
discussions, and Dr. Jodi Nunnari for a careful reading of our manuscript. We also
thank Dr. Alan Howe, Dr. Sohum Mehta, and Dr. Jin Zhang for providing plasmids used
in this study. This project was funded by NIH Grants R01NS114210 and R21NS101648
(J.S.T.), and F32NS108519 (N.C.V.).
article_number: '5231'
article_processing_charge: Yes
article_type: original
author:
- first_name: Nicholas C.
full_name: Vierra, Nicholas C.
last_name: Vierra
- first_name: Luisa
full_name: Ribeiro-Silva, Luisa
last_name: Ribeiro-Silva
- first_name: Michael
full_name: Kirmiz, Michael
last_name: Kirmiz
- first_name: Deborah
full_name: Van Der List, Deborah
last_name: Van Der List
- first_name: Pradeep
full_name: Bhandari, Pradeep
id: 45EDD1BC-F248-11E8-B48F-1D18A9856A87
last_name: Bhandari
orcid: 0000-0003-0863-4481
- first_name: Olivia A.
full_name: Mack, Olivia A.
last_name: Mack
- first_name: James
full_name: Carroll, James
last_name: Carroll
- first_name: Elodie
full_name: Le Monnier, Elodie
id: 3B59276A-F248-11E8-B48F-1D18A9856A87
last_name: Le Monnier
- first_name: Sue A.
full_name: Aicher, Sue A.
last_name: Aicher
- first_name: Ryuichi
full_name: Shigemoto, Ryuichi
id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
last_name: Shigemoto
orcid: 0000-0001-8761-9444
- first_name: James S.
full_name: Trimmer, James S.
last_name: Trimmer
citation:
ama: Vierra NC, Ribeiro-Silva L, Kirmiz M, et al. Neuronal ER-plasma membrane junctions
couple excitation to Ca2+-activated PKA signaling. Nature Communications.
2023;14. doi:10.1038/s41467-023-40930-6
apa: Vierra, N. C., Ribeiro-Silva, L., Kirmiz, M., Van Der List, D., Bhandari, P.,
Mack, O. A., … Trimmer, J. S. (2023). Neuronal ER-plasma membrane junctions couple
excitation to Ca2+-activated PKA signaling. Nature Communications. Springer
Nature. https://doi.org/10.1038/s41467-023-40930-6
chicago: Vierra, Nicholas C., Luisa Ribeiro-Silva, Michael Kirmiz, Deborah Van Der
List, Pradeep Bhandari, Olivia A. Mack, James Carroll, et al. “Neuronal ER-Plasma
Membrane Junctions Couple Excitation to Ca2+-Activated PKA Signaling.” Nature
Communications. Springer Nature, 2023. https://doi.org/10.1038/s41467-023-40930-6.
ieee: N. C. Vierra et al., “Neuronal ER-plasma membrane junctions couple
excitation to Ca2+-activated PKA signaling,” Nature Communications, vol.
14. Springer Nature, 2023.
ista: Vierra NC, Ribeiro-Silva L, Kirmiz M, Van Der List D, Bhandari P, Mack OA,
Carroll J, Le Monnier E, Aicher SA, Shigemoto R, Trimmer JS. 2023. Neuronal ER-plasma
membrane junctions couple excitation to Ca2+-activated PKA signaling. Nature Communications.
14, 5231.
mla: Vierra, Nicholas C., et al. “Neuronal ER-Plasma Membrane Junctions Couple Excitation
to Ca2+-Activated PKA Signaling.” Nature Communications, vol. 14, 5231,
Springer Nature, 2023, doi:10.1038/s41467-023-40930-6.
short: N.C. Vierra, L. Ribeiro-Silva, M. Kirmiz, D. Van Der List, P. Bhandari, O.A.
Mack, J. Carroll, E. Le Monnier, S.A. Aicher, R. Shigemoto, J.S. Trimmer, Nature
Communications 14 (2023).
date_created: 2023-09-03T22:01:14Z
date_published: 2023-08-26T00:00:00Z
date_updated: 2023-09-06T06:53:32Z
day: '26'
ddc:
- '570'
department:
- _id: RySh
doi: 10.1038/s41467-023-40930-6
external_id:
pmid:
- '37633939'
file:
- access_level: open_access
checksum: 6ab8aab4e957f626a09a1c73db3388fb
content_type: application/pdf
creator: dernst
date_created: 2023-09-06T06:50:07Z
date_updated: 2023-09-06T06:50:07Z
file_id: '14270'
file_name: 2023_NatureComm_Vierra.pdf
file_size: 9412549
relation: main_file
success: 1
file_date_updated: 2023-09-06T06:50:07Z
has_accepted_license: '1'
intvolume: ' 14'
language:
- iso: eng
month: '08'
oa: 1
oa_version: Published Version
pmid: 1
publication: Nature Communications
publication_identifier:
eissn:
- 2041-1723
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
scopus_import: '1'
status: public
title: Neuronal ER-plasma membrane junctions couple excitation to Ca2+-activated PKA
signaling
tmp:
image: /images/cc_by.png
legal_code_url: https://creativecommons.org/licenses/by/4.0/legalcode
name: Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)
short: CC BY (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 14
year: '2023'
...