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  3. Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1.
 

Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1.

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BORIS DOI
10.48350/183467
Date of Publication
August 16, 2023
Publication Type
Article
Division/Institute

Department for BioMed...

Institut für Anatomie...

Universitätsklinik fü...

Department for BioMed...

Department for BioMed...

Department for BioMed...

Author
Pilotto, Federica
Department for BioMedical Research, Forschungsgruppe Neurologie
Universitätsklinik für Neurologie
Douthwaite, Christopher
Diab, Rim
Universitätsklinik für Neurologie
Department for BioMedical Research, Forschungsgruppe Neurologie
Ye, XiaoQian
Al Qassab, Zahraa Ahmed Mohammed
Department for BioMedical Research (DBMR)
Tietje, Christoph
Mounassir, Meriem
Odriozola Quesada, Adolfo
Institut für Anatomie
Institut für Anatomie - Topographische & Klinische Anatomie
Thapa, Aishwarya
Department for BioMedical Research (DBMR)
Buijsen, Ronald A M
Lagache, Sophie
Uldry, Anne-Christine
Department for BioMedical Research, Proteomik und Massenspektrometrie (PMS)
Heller, Manfredorcid-logo
Department for BioMedical Research, Proteomik und Massenspektrometrie (PMS)
Müller, Stefan Jürg
Department for BioMedical Research, Durchflusszytometrie und Zellsortierung
van Roon-Mom, Willeke M C
Zuber, Benoîtorcid-logo
Institut für Anatomie
Liebscher, Sabine
Saxena, Smitaorcid-logo
Universitätsklinik für Neurologie
Department for BioMedical Research, Forschungsgruppe Neurologie
Subject(s)

600 - Technology::610...

500 - Science::570 - ...

Series
Neuron
ISSN or ISBN (if monograph)
1097-4199
Publisher
Elsevier
Language
English
Publisher DOI
10.1016/j.neuron.2023.05.016
PubMed ID
37321222
Uncontrolled Keywords

GABAergic neurons Pur...

spinocerebellar ataxi...

Description
Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using in vivo two-photon imaging in behaving spinocerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory circuit element (molecular layer interneurons [MLINs]) that becomes prematurely hyperexcitable, compromising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcitable MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibition of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level deficits upstream of PNs are one of the main disease triggers in SCA1.
Handle
https://boris-portal.unibe.ch/handle/20.500.12422/167885
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1-s2.0-S0896627323003896-main.pdftextAdobe PDF9.55 MBpublishedOpen
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