Early molecular layer interneuron hyperactivity triggers Purkinje neuron degeneration in SCA1

Neuron, vol. 111, pp. 2523–2543.e10

Abstract

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.

Authors 17

1. Federica Pilotto

   University of Bern · University Hospital of Bern

   Affiliation as printed

   Department of Neurology, Inselspital University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland

   Department for BioMedical Research, University of Bern, Bern, Switzerland

   Department of Neurology, Inselspital University Hospital, Bern, Switzerland

2. Christopher Douthwaite

   Institut für Klinische Neuroimmunologie · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig-Maximilians University Munich, Martinsried, Germany

3. Rim Diab

   University of Bern · University Hospital of Bern

   Affiliation as printed

   Department of Neurology, Inselspital University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland

   Department for BioMedical Research, University of Bern, Bern, Switzerland

   Department of Neurology, Inselspital University Hospital, Bern, Switzerland

4. XiaoQian Ye

   Institut für Klinische Neuroimmunologie · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig-Maximilians University Munich, Martinsried, Germany

5. Zahraa Al qassab

   University of Bern · University Hospital of Bern

   Affiliation as printed

   Department of Neurology, Inselspital University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland

   Department for BioMedical Research, University of Bern, Bern, Switzerland

   Department of Neurology, Inselspital University Hospital, Bern, Switzerland

6. Christoph Tietje

   Institut für Klinische Neuroimmunologie · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig-Maximilians University Munich, Martinsried, Germany

7. Meriem Mounassir

   Institut für Klinische Neuroimmunologie · Ludwig-Maximilians-Universität München

   Affiliation as printed

   Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig-Maximilians University Munich, Martinsried, Germany

8. Adolfo Odriozola

   University of Bern

   Affiliation as printed

   Institute of Anatomy, University of Bern, Bern, Switzerland

9. Ronald A.M. Buijsen Aachen Department of Human Genetics

   Leiden University Medical Center

   Affiliation as printed

   Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

10. Sophie Braga Lagache

    University of Bern

    Affiliation as printed

    Proteomics and Mass Spectrometry Core Facility, Department for BioMedical Research, University of Bern, Bern, Switzerland

11. Anne‐Christine Uldry

    University of Bern

    Affiliation as printed

    Proteomics and Mass Spectrometry Core Facility, Department for BioMedical Research, University of Bern, Bern, Switzerland

12. Manfred Heller

    University of Bern

    Affiliation as printed

    Proteomics and Mass Spectrometry Core Facility, Department for BioMedical Research, University of Bern, Bern, Switzerland

13. Stefan Müller

    University of Bern

    Affiliation as printed

    Flow Cytometry and Cell sorting, Department for BioMedical Research, University of Bern, Bern, Switzerland

14. Willeke van Roon‐Mom Aachen Department of Human Genetics

    Leiden University Medical Center

    Affiliation as printed

    Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

15. Benoît Zuber

    University of Bern

    Affiliation as printed

    Institute of Anatomy, University of Bern, Bern, Switzerland

16. Sabine Liebscher corresponding

    Munich Cluster for Systems Neurology · University Hospital Cologne · Institut für Klinische Neuroimmunologie · Ludwig-Maximilians-Universität München

    Affiliation as printed

    Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig-Maximilians University Munich, Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; University Hospital Cologne, Deptartment of Neurology, Cologne, Germany. Electronic address: sabine.liebscher@med.uni-muenchen.de

    Institute of Clinical Neuroimmunology, Klinikum der Universität München, Ludwig-Maximilians University Munich, Martinsried, Germany

    Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    University Hospital Cologne, Deptartment of Neurology, Cologne, Germany

17. Smita Saxena corresponding

    University of Bern · University Hospital of Bern

    Affiliation as printed

    Department of Neurology, Inselspital University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland. Electronic address: smita.saxena@dbmr.unibe.ch

    Department for BioMedical Research, University of Bern, Bern, Switzerland

    Department of Neurology, Inselspital University Hospital, Bern, Switzerland