Defective synaptic transmission causes disease signs in a mouse model of Juvenile Neuronal Ceroid Lipofuscinosis

  1. Benedikt Grünewald
  2. Maren D Lange
  3. Christian Werner
  4. Aet O'Leary
  5. Andreas Weishaupt
  6. Sandy Popp
  7. David A Pearce
  8. Heinz Wiendl
  9. Andreas Reif
  10. Hans C Pape
  11. Klaus V Toyka
  12. Claudia Sommer
  13. Christian Geis  Is a corresponding author
  1. Jena University Hospital, Germany
  2. University of Münster, Germany
  3. University Hospital Frankfurt, Germany
  4. University Hospital Würzburg, Germany
  5. Sanford Research, United States

Abstract

Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3Δex7/8) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in amygdala, hippocampus, and in cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.

Article and author information

Author details

  1. Benedikt Grünewald

    Hans-Berger Department of Neurology, Jena University Hospital, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Maren D Lange

    Institute of Physiology I, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Christian Werner

    Hans-Berger Department of Neurology, Jena University Hospital, Jena, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Aet O'Leary

    Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6783-4729
  5. Andreas Weishaupt

    Department of Neurology, University Hospital Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Sandy Popp

    Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. David A Pearce

    Sanford Children´s Health Research Center, Sanford Research, Sioux Falls, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Heinz Wiendl

    Department of Neurology, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  9. Andreas Reif

    Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt, Germany
    Competing interests
    The authors declare that no competing interests exist.
  10. Hans C Pape

    Institute of Physiology I, University of Münster, Münster, Germany
    Competing interests
    The authors declare that no competing interests exist.
  11. Klaus V Toyka

    Department of Neurology, University Hospital Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Claudia Sommer

    Department of Neurology, University Hospital Würzburg, Würzburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Christian Geis

    Hans-Berger Department of Neurology, Jena University Hospital, Jena, Germany
    For correspondence
    christian.geis@med.uni-jena.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9859-581X

Funding

Deutsche Forschungsgemeinschaft (SFB 581 [TP A7])

  • Klaus V Toyka
  • Claudia Sommer

Deutsche Forschungsgemeinschaft (SFB/TR 166 [B2])

  • Christian Geis

Deutsche Forschungsgemeinschaft (SFB/TR 58)

  • Maren D Lange
  • Hans C Pape

German Federal Ministry of Education and Research (Center for Sepsis Control and Care)

  • Christian Geis

IZKF University Hospital Jena

  • Benedikt Grünewald
  • Christian Geis

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All animal experiments were approved by the respective Bavarian and Thuringian state authorities (No. 55.5-2531.01-12/10; 78/05 and 02-44/12). All efforts were made to minimize animal suffering and to reduce the number of animals used. The study was performed in accordance with the ARRIVE guidelines for reporting animal research (Kilkenny et al., 2010).

Reviewing Editor

  1. Christian Rosenmund, Charité-Universitätsmedizin Berlin, Germany

Publication history

  1. Received: May 19, 2017
  2. Accepted: November 13, 2017
  3. Accepted Manuscript published: November 14, 2017 (version 1)
  4. Version of Record published: November 21, 2017 (version 2)

Copyright

© 2017, Grünewald et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Benedikt Grünewald
  2. Maren D Lange
  3. Christian Werner
  4. Aet O'Leary
  5. Andreas Weishaupt
  6. Sandy Popp
  7. David A Pearce
  8. Heinz Wiendl
  9. Andreas Reif
  10. Hans C Pape
  11. Klaus V Toyka
  12. Claudia Sommer
  13. Christian Geis
(2017)
Defective synaptic transmission causes disease signs in a mouse model of Juvenile Neuronal Ceroid Lipofuscinosis
eLife 6:e28685.
https://doi.org/10.7554/eLife.28685

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