---
_id: '9330'
abstract:
- lang: eng
text: In nerve cells the genes encoding for α2δ subunits of voltage-gated calcium
channels have been linked to synaptic functions and neurological disease. Here
we show that α2δ subunits are essential for the formation and organization of
glutamatergic synapses. Using a cellular α2δ subunit triple-knockout/knockdown
model, we demonstrate a failure in presynaptic differentiation evidenced by defective
presynaptic calcium channel clustering and calcium influx, smaller presynaptic
active zones, and a strongly reduced accumulation of presynaptic vesicle-associated
proteins (synapsin and vGLUT). The presynaptic defect is associated with the downscaling
of postsynaptic AMPA receptors and the postsynaptic density. The role of α2δ isoforms
as synaptic organizers is highly redundant, as each individual α2δ isoform can
rescue presynaptic calcium channel trafficking and expression of synaptic proteins.
Moreover, α2δ-2 and α2δ-3 with mutated metal ion-dependent adhesion sites can
fully rescue presynaptic synapsin expression but only partially calcium channel
trafficking, suggesting that the regulatory role of α2δ subunits is independent
from its role as a calcium channel subunit. Our findings influence the current
view on excitatory synapse formation. First, our study suggests that postsynaptic
differentiation is secondary to presynaptic differentiation. Second, the dependence
of presynaptic differentiation on α2δ implicates α2δ subunits as potential nucleation
points for the organization of synapses. Finally, our results suggest that α2δ
subunits act as transsynaptic organizers of glutamatergic synapses, thereby aligning
the synaptic active zone with the postsynaptic density.
acknowledged_ssus:
- _id: EM-Fac
acknowledgement: "We thank Arnold Schwartz for providing α2δ-1 knockout mice; Ariane
Benedetti, Sabine Baumgartner, Sandra Demetz, and Irene Mahlknecht for technical
support; Nadine Ortner and Andreas Lieb for electrophysiological experiments; the
team of the Electron Microscopy Facility at the Institute of Science and Technology
Austria for technical support related to ultrastructural analysis; Hermann Dietrich
and Anja Beierfuß and her team for animal care; Jutta Engel and Jörg Striessnig
for critical discussions; and Bruno Benedetti and Bernhard Flucher for critical
discussions and reading the manuscript. This study was supported by Austrian Science
Fund Grants P24079, F44060, F44150, and DOC30-B30 (to G.J.O.) and T855 (to M.C.),
European Research Council Grant AdG 694539 (to R.S.), Deutsche Forschungsgemeinschaft\r\nGrant
SFB1348-TP A03 (to M.M.), and Interdisziplinäre Zentrum für Klinische Forschung
Münster Grant Mi3/004/19 (to M.M.). This work is part of the PhD theses of C.L.S.,
S.M.G., and C.A."
article_processing_charge: No
article_type: original
author:
- first_name: Clemens L.
full_name: Schöpf, Clemens L.
last_name: Schöpf
- first_name: Cornelia
full_name: Ablinger, Cornelia
last_name: Ablinger
- first_name: Stefanie M.
full_name: Geisler, Stefanie M.
last_name: Geisler
- first_name: Ruslan I.
full_name: Stanika, Ruslan I.
last_name: Stanika
- first_name: Marta
full_name: Campiglio, Marta
last_name: Campiglio
- first_name: Walter
full_name: Kaufmann, Walter
id: 3F99E422-F248-11E8-B48F-1D18A9856A87
last_name: Kaufmann
orcid: 0000-0001-9735-5315
- first_name: Benedikt
full_name: Nimmervoll, Benedikt
last_name: Nimmervoll
- first_name: Bettina
full_name: Schlick, Bettina
last_name: Schlick
- first_name: Johannes
full_name: Brockhaus, Johannes
last_name: Brockhaus
- first_name: Markus
full_name: Missler, Markus
last_name: Missler
- first_name: Ryuichi
full_name: Shigemoto, Ryuichi
id: 499F3ABC-F248-11E8-B48F-1D18A9856A87
last_name: Shigemoto
orcid: 0000-0001-8761-9444
- first_name: Gerald J.
full_name: Obermair, Gerald J.
last_name: Obermair
citation:
ama: Schöpf CL, Ablinger C, Geisler SM, et al. Presynaptic α2δ subunits are key
organizers of glutamatergic synapses. PNAS. 2021;118(14). doi:10.1073/pnas.1920827118
apa: Schöpf, C. L., Ablinger, C., Geisler, S. M., Stanika, R. I., Campiglio, M.,
Kaufmann, W., … Obermair, G. J. (2021). Presynaptic α2δ subunits are key organizers
of glutamatergic synapses. PNAS. National Academy of Sciences. https://doi.org/10.1073/pnas.1920827118
chicago: Schöpf, Clemens L., Cornelia Ablinger, Stefanie M. Geisler, Ruslan I. Stanika,
Marta Campiglio, Walter Kaufmann, Benedikt Nimmervoll, et al. “Presynaptic Α2δ
Subunits Are Key Organizers of Glutamatergic Synapses.” PNAS. National
Academy of Sciences, 2021. https://doi.org/10.1073/pnas.1920827118.
ieee: C. L. Schöpf et al., “Presynaptic α2δ subunits are key organizers of
glutamatergic synapses,” PNAS, vol. 118, no. 14. National Academy of Sciences,
2021.
ista: Schöpf CL, Ablinger C, Geisler SM, Stanika RI, Campiglio M, Kaufmann W, Nimmervoll
B, Schlick B, Brockhaus J, Missler M, Shigemoto R, Obermair GJ. 2021. Presynaptic
α2δ subunits are key organizers of glutamatergic synapses. PNAS. 118(14).
mla: Schöpf, Clemens L., et al. “Presynaptic Α2δ Subunits Are Key Organizers of
Glutamatergic Synapses.” PNAS, vol. 118, no. 14, National Academy of Sciences,
2021, doi:10.1073/pnas.1920827118.
short: C.L. Schöpf, C. Ablinger, S.M. Geisler, R.I. Stanika, M. Campiglio, W. Kaufmann,
B. Nimmervoll, B. Schlick, J. Brockhaus, M. Missler, R. Shigemoto, G.J. Obermair,
PNAS 118 (2021).
date_created: 2021-04-18T22:01:40Z
date_published: 2021-04-06T00:00:00Z
date_updated: 2023-08-08T13:08:47Z
day: '06'
ddc:
- '570'
department:
- _id: EM-Fac
- _id: RySh
doi: 10.1073/pnas.1920827118
ec_funded: 1
external_id:
isi:
- '000637398300002'
file:
- access_level: open_access
checksum: dd014f68ae9d7d8d8fc4139a24e04506
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creator: dernst
date_created: 2021-04-19T10:10:56Z
date_updated: 2021-04-19T10:10:56Z
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file_name: 2021_PNAS_Schoepf.pdf
file_size: 2603911
relation: main_file
success: 1
file_date_updated: 2021-04-19T10:10:56Z
has_accepted_license: '1'
intvolume: ' 118'
isi: 1
issue: '14'
language:
- iso: eng
license: https://creativecommons.org/licenses/by/4.0/
month: '04'
oa: 1
oa_version: Published Version
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'
publication: PNAS
publication_identifier:
eissn:
- 1091-6490
publication_status: published
publisher: National Academy of Sciences
quality_controlled: '1'
scopus_import: '1'
status: public
title: Presynaptic α2δ subunits are key organizers of glutamatergic synapses
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: 4359f0d1-fa6c-11eb-b949-802e58b17ae8
volume: 118
year: '2021'
...