Abstract |
Huntington's disease (HD) is a severe genetically inherited neurodegenerative disorder. Patients present with three principal phenotypes of motor symptoms: choreatic, hypokinetic-rigid and mixed. The Q175 mouse model of disease offers an opportunity to investigate the cellular basis of the hypokinetic-rigid form of HD. At the age of 1 year homozygote Q175 mice exhibited the following signs of hypokinesia: Reduced frequency of spontaneous movements on a precision balance at daytime (-55%), increased total time spent without movement in an open field (+42%), failures in the execution of unconditioned avoidance reactions (+32%), reduced ability for conditioned avoidance (-96%) and increased reaction times (+65%) in a shuttle box. Local field potential recordings revealed low-frequency gamma oscillations in the striatum as a characteristic feature of HD mice at rest. There was no significant loss of DARPP-32 immunolabeled striatal projection neurons (SPNs) although the level of DARPP-32 immunoreactivity was lower in HD. As a potential cause of hypokinesia, HD mice revealed a strong reduction in striatal KCl-induced dopamine release, accompanied by a decrease in the number of tyrosine hydroxylase-(TH)- and VMAT2-positive synaptic varicosities. The presynaptic TH fluorescence level was also reduced. Patch-clamp experiments were performed in slices from 1-year-old mice to record unitary EPSCs (uEPSCs) of presumed cortical origin in the absence of G-protein-mediated modulation. In HD mice, the maximal amplitudes of uEPSCs amounted to 69% of the WT level which matches the loss of VGluT1+/SYP+ synaptic terminals in immunostained sections. These results identify impairment of cortico-striatal synaptic transmission and dopamine release as a potential basis of hypokinesia in HD.
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Authors | T Rothe, M Deliano, A M Wójtowicz, A Dvorzhak, D Harnack, S Paul, T Vagner, I Melnick, H Stark, R Grantyn |
Journal | Neuroscience
(Neuroscience)
Vol. 311
Pg. 519-38
(Dec 17 2015)
ISSN: 1873-7544 [Electronic] United States |
PMID | 26546830
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved. |
Chemical References |
- Dopamine and cAMP-Regulated Phosphoprotein 32
- Ppp1r1b protein, mouse
- Slc18a2 protein, mouse
- Vesicular Monoamine Transport Proteins
- Tyrosine 3-Monooxygenase
- Dopamine
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Topics |
- Animals
- Corpus Striatum
(pathology, physiopathology)
- Disease Models, Animal
- Dopamine
(metabolism)
- Dopamine and cAMP-Regulated Phosphoprotein 32
(metabolism)
- Excitatory Postsynaptic Potentials
(physiology)
- Gamma Rhythm
(physiology)
- Humans
- Huntington Disease
(pathology, physiopathology)
- Male
- Mice, Transgenic
- Motor Activity
(physiology)
- Synapses
(pathology, physiology)
- Synaptic Transmission
(physiology)
- Tissue Culture Techniques
- Tyrosine 3-Monooxygenase
(metabolism)
- Vesicular Monoamine Transport Proteins
(metabolism)
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