TY  - JOUR
A1  - Grünewald, Benedikt
A1  - Lange, Maren D
A1  - Werner, Christian
A1  - O'Leary, Aet
A1  - Weishaupt, Andreas
A1  - Popp, Sandy
A1  - Pearce, David A
A1  - Wiendl, Heinz
A1  - Reif, Andreas
A1  - Pape, Hans C
A1  - Toyka, Klaus V
A1  - Sommer, Claudia
A1  - Geis, Christian
T1  - Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis
JF  - eLife
N2  - 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 (Cln3\(^{Δex1-6}\)) 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.
KW  - CLN3
KW  - mutation
KW  - mouse model
KW  - synaptic transmission
KW  - amygdala
KW  - hippocampus
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170004
VL  - 6
IS  - e28685
ER  - 
TY  - JOUR
A1  - Simon, Christian M.
A1  - Rauskolb, Stefanie
A1  - Gunnersen, Jennifer M.
A1  - Holtmann, Bettina
A1  - Drepper, Carsten
A1  - Dombert, Benjamin
A1  - Braga, Massimiliano
A1  - Wiese, Stefan
A1  - Jablonka, Sibylle
A1  - Pühringer, Dirk
A1  - Zielasek, Jürgen
A1  - Hoeflich, Andreas
A1  - Silani, Vincenzo
A1  - Wolf, Eckhard
A1  - Kneitz, Susanne
A1  - Sommer, Claudia
A1  - Toyka, Klaus V.
A1  - Sendtner, Michael
T1  - Dysregulated IGFBP5 expression causes axon degeneration and motoneuron loss in diabetic neuropathy
JF  - Acta Neuropathologica
N2  - Diabetic neuropathy (DNP), afflicting sensory and motor nerve fibers, is a major complication in diabetes.The underlying cellular mechanisms of axon degeneration are poorly understood. IGFBP5, an inhibitory binding protein for insulin-like growth factor 1 (IGF1) is highly up-regulated in nerve biopsies of patients with DNP. We investigated the pathogenic relevance of this finding in transgenic mice overexpressing IGFBP5 in motor axons and sensory nerve fibers. These mice develop motor axonopathy and sensory deficits similar to those seen in DNP. Motor axon degeneration was also observed in mice in which the IGF1 receptor(IGF1R) was conditionally depleted in motoneurons, indicating that reduced activity of IGF1 on IGF1R in motoneurons is responsible for the observed effect. These data provide evidence that elevated expression of IGFBP5 in diabetic nerves reduces the availability of IGF1 for IGF1R on motor axons, thus leading to progressive neurodegeneration. Inhibition of IGFBP5 could thus offer novel treatment strategies for DNP.
KW  - Motor nerve biopsy
KW  - Diabetic polyneuropathy
KW  - Neuropathy
KW  - Neurotrophic factors
KW  - Axonal degeneration
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-154569
VL  - 130
SP  - 373
EP  - 387
ER  -