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.

Reviewing Editor

  1. Christian Rosenmund, Charité-Universitätsmedizin Berlin, Germany

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).

Version 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.

Metrics

  • 1,931
    views
  • 293
    downloads
  • 28
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.28685

Further reading

    1. Neuroscience
    Alexandra L Jellinger, Rebecca L Suthard ... Steve Ramirez
    Research Article

    Negative memories engage a brain and body-wide stress response in humans that can alter cognition and behavior. Prolonged stress responses induce maladaptive cellular, circuit, and systems-level changes that can lead to pathological brain states and corresponding disorders in which mood and memory are affected. However, it is unclear if repeated activation of cells processing negative memories induces similar phenotypes in mice. In this study, we used an activity-dependent tagging method to access neuronal ensembles and assess their molecular characteristics. Sequencing memory engrams in mice revealed that positive (male-to-female exposure) and negative (foot shock) cells upregulated genes linked to anti- and pro-inflammatory responses, respectively. To investigate the impact of persistent activation of negative engrams, we chemogenetically activated them in the ventral hippocampus over 3 months and conducted anxiety and memory-related tests. Negative engram activation increased anxiety behaviors in both 6- and 14-month-old mice, reduced spatial working memory in older mice, impaired fear extinction in younger mice, and heightened fear generalization in both age groups. Immunohistochemistry revealed changes in microglial and astrocytic structure and number in the hippocampus. In summary, repeated activation of negative memories induces lasting cellular and behavioral abnormalities in mice, offering insights into the negative effects of chronic negative thinking-like behaviors on human health.

    1. Neuroscience
    Alexandra H Leighton, Juliette E Cheyne, Christian Lohmann
    Research Article

    Synaptic inputs to cortical neurons are highly structured in adult sensory systems, such that neighboring synapses along dendrites are activated by similar stimuli. This organization of synaptic inputs, called synaptic clustering, is required for high-fidelity signal processing, and clustered synapses can already be observed before eye opening. However, how clustered inputs emerge during development is unknown. Here, we employed concurrent in vivo whole-cell patch-clamp and dendritic calcium imaging to map spontaneous synaptic inputs to dendrites of layer 2/3 neurons in the mouse primary visual cortex during the second postnatal week until eye opening. We found that the number of functional synapses and the frequency of transmission events increase several fold during this developmental period. At the beginning of the second postnatal week, synapses assemble specifically in confined dendritic segments, whereas other segments are devoid of synapses. By the end of the second postnatal week, just before eye opening, dendrites are almost entirely covered by domains of co-active synapses. Finally, co-activity with their neighbor synapses correlates with synaptic stabilization and potentiation. Thus, clustered synapses form in distinct functional domains presumably to equip dendrites with computational modules for high-capacity sensory processing when the eyes open.