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.
Metrics
-
- 2,014
- views
-
- 310
- downloads
-
- 29
- 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)
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
Further reading
-
- Neuroscience
Intrinsic sensory neurons are an essential part of the enteric nervous system (ENS) and play a crucial role in gastrointestinal tract motility and digestion. Neuronal subtypes in the ENS have been distinguished by their electrophysiological properties, morphology, and expression of characteristic markers, notably neurotransmitters and neuropeptides. Here, we investigated synaptic cell adhesion molecules as novel cell-type markers in the ENS. Our work identifies two type II classic cadherins, Cdh6 and Cdh8, specific to sensory neurons in the mouse colon. We show that Cdh6+ neurons demonstrate all other distinguishing classifications of enteric sensory neurons including marker expression of Calcb and Nmu, Dogiel type II morphology and AH-type electrophysiology and IH current. Optogenetic activation of Cdh6+ sensory neurons in distal colon evokes retrograde colonic motor complexes (CMCs), while pharmacologic blockade of rhythmicity-associated current IH disrupts the spontaneous generation of CMCs. These findings provide the first demonstration of selective activation of a single neurochemical and functional class of enteric neurons and demonstrate a functional and critical role for sensory neurons in the generation of CMCs.
-
- Neuroscience
What determines where to move the eyes? We recently showed that pupil size, a well-established marker of effort, also reflects the effort associated with making a saccade (‘saccade costs’). Here, we demonstrate saccade costs to critically drive saccade selection: when choosing between any two saccade directions, the least costly direction was consistently preferred. Strikingly, this principle even held during search in natural scenes in two additional experiments. When increasing cognitive demand experimentally through an auditory counting task, participants made fewer saccades and especially cut costly directions. This suggests that the eye-movement system and other cognitive operations consume similar resources that are flexibly allocated among each other as cognitive demand changes. Together, we argue that eye-movement behavior is tuned to adaptively minimize saccade-inherent effort.
