Defective synaptic transmission causes disease signs in a mouse model of Juvenile Neuronal Ceroid Lipofuscinosis
- Jena University Hospital, Germany
- University of Münster, Germany
- University Hospital Frankfurt, Germany
- University Hospital Würzburg, Germany
- 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
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).
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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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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