Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis

• Published in: eLife 2017-11, Vol.6
• Main Authors: Grünewald, Benedikt, Lange, Maren D, Werner, Christian, O'Leary, Aet, Weishaupt, Andreas, Popp, Sandy, Pearce, David A, Wiendl, Heinz, Reif, Andreas, Pape, Hans C, Toyka, Klaus V, Sommer, Claudia, Geis, Christian
• Format: Article
• Language: English
• Subjects: Age; Amygdala; Amygdala - physiopathology; Animals; Anxiety; Ataxia; Batten disease; Brain; Calbindin; Central nervous system; Cerebellum; Cerebellum - physiopathology; Childhood; Children; cln3; CLN3 protein; Death; Disease Models, Animal; Disease transmission; Diseases; GABA; Gene Knockout Techniques; Genes; Genetic aspects; Germany; Glutamate decarboxylase; Hippocampus; Hippocampus - physiopathology; Interneurons; Membrane Glycoproteins - deficiency; Mice; Mice, Knockout; Molecular Chaperones; Mutation; Nerve Net - physiopathology; Nervous system diseases; Neurodegeneration; Neurology; Neuronal ceroid lipofuscinosis; Neuronal Ceroid-Lipofuscinoses - pathology; Neuronal Ceroid-Lipofuscinoses - physiopathology; Neurons; Neuropeptide Y; Neuropeptides; Neurophysiology; Neuroscience; Parvalbumin; Patch-Clamp Techniques; Pediatric diseases; Psychotherapy; Rodents; Software; Statistical analysis; synaptic dysfunction; Synaptic Transmission; γ-Aminobutyric acid
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.28685

Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used knockout ( 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 the amygdala, hippocampus, and 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.