title: Early GABAergic transmission defects in the external globus pallidus and rest/activity rhythm alteration in a mouse model of Huntington's disease.
abstract: Huntington'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.
authors.affiliation: Univ. Bordeaux, INCIA, UMR 5287, F-33000 Bordeaux, France; CNRS, INCIA, UMR 5287, F-33000 Bordeaux, France.
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Du
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Chazalon
authors.affiliation: Univ. Bordeaux, INCIA, UMR 5287, F-33000 Bordeaux, France; CNRS, INCIA, UMR 5287, F-33000 Bordeaux, France.
authors.forename: Emma
authors.initials: E
authors.lastname: Bestaven
authors.affiliation: INSERM, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France; University of Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U862, F-33000 Bordeaux, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Leste-Lasserre
authors.affiliation: Univ. de Bordeaux, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France; CNRS, Institut des Maladies Neurodégénératives, UMR 5293, F-33000 Bordeaux, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Baufreton
authors.affiliation: Univ. Bordeaux, INCIA, UMR 5287, F-33000 Bordeaux, France; CNRS, INCIA, UMR 5287, F-33000 Bordeaux, France.
authors.forename: Jean-René
authors.initials: JR
authors.lastname: Cazalets
authors.affiliation: Univ. Bordeaux, INCIA, UMR 5287, F-33000 Bordeaux, France; CNRS, INCIA, UMR 5287, F-33000 Bordeaux, France.
authors.forename: Yoon H
authors.initials: YH
authors.lastname: Cho
authors.affiliation: Univ. Bordeaux, INCIA, UMR 5287, F-33000 Bordeaux, France; CNRS, INCIA, UMR 5287, F-33000 Bordeaux, France. Electronic address: maurice.garret@u-bordeaux.fr.
authors.forename: Maurice
authors.initials: M
authors.lastname: Garret
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D005917:Globus Pallidus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000378:metabolism* / Q000473:pathology; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055369:Miniature Postsynaptic Potentials / Q000502:physiology; D009043:Motor Activity / Q000502:physiology*; D012890:Sleep / Q000502:physiology*; D013569:Synapses / Q000378:metabolism*; D046509:Tissue Culture Techniques; D019680:Trinucleotide Repeat Expansion; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D005680:gamma-Aminobutyric Acid
keywords: basal ganglia; disease progression; inhibitory post-synaptic currents; locomotor activity; rest/activity fragmentation; synapse