• Zhuowei Du, Marine Chazalon, Emma Bestaven, Thierry Leste-Lasserre, Jérôme Baufreton, Jean-René Cazalets, Yoon H Cho, and Maurice Garret.
• Univ. Bordeaux, INCIA, UMR 5287, F-33000 Bordeaux, France; CNRS, INCIA, UMR 5287, F-33000 Bordeaux, France.
• Neuroscience. 2016 Aug 4; 329: 363-79.

AbstractHuntington's disease (HD) is characterized by progressive motor symptoms preceded by cognitive deficits and is regarded as a disorder that primarily affects the basal ganglia. The external globus pallidus (GPe) has a central role in the basal ganglia, projects directly to the cortex, and is majorly modulated by GABA. To gain a better understanding of the time course of HD progression and gain insight into the underlying mechanisms, we analyzed GABAergic neurotransmission in the GPe of the R6/1 mouse model at purportedly asymptomatic and symptomatic stages (i.e., 2 and 6months). Western blot and quantitative polymerase chain reaction (PCR) analyses revealed alterations in the GPe of male R6/1 mice compared with wild-type littermates. Expression of proteins involved in pre- and post-synaptic GABAergic compartments as well as synapse number were severely decreased at 2 and 6months. At both ages, patch-clamp electrophysiological recordings showed a decrease of spontaneous and miniature inhibitory post-synaptic currents (IPSCs) suggesting that HD mutation has an early effect on the GABA signaling in the brain. Therefore, we performed continuous locomotor activity recordings from 2 to 4months of age. Actigraphy analyses revealed rest/activity fragmentation alterations that parallel GABAergic system impairment at 2months, while the locomotor deficit is evident only at 3months in R6/1 mice. Our results reveal early deficits in HD and support growing evidence for a critical role played by the GPe in physiological and pathophysiological states. We suggest that actimetry may be used as a non-invasive tool to monitor early disease progression.Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

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