Metabolic and electrophysiological changes in the basal ganglia of transgenic Huntington's disease rats

Neurobiology of Disease

Harry W.M. Steinbusch¹  Abdelhamid Benazzouz²  Yasin Temel³  Marcus L.F. Janssen³  Jonathan Chetrit⁴  Rinske Vlamings⁵  Stephan von Hörsten⁵  Veerle Visser-Vandewalle⁶  Ramazan Kozan⁶ 

[1] Department of Biomedical Sciences, University of Sheffield, Sheffield, United Kingdom;Departments of Neurosurgery, Maastricht University Medical Center, Maastricht, The Netherlands;European Graduate School of Neuroscience (EURON), Maastricht, The Netherlands;Université de Bordeaux, Institut des Maladies Neurodégénératives, CNRS UMR 5293, Bordeaux, France;Department of Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands;Université de Bordeaux, Institut des Maladies Neurodégénératives, CNRS UMR 5293, Bordeaux, France;

关键词: Huntington's disease;    Basal ganglia;    Transgenic rat;    Cytochrome oxidase;    PGC-1 alpha;    Electrophysiology;   

DOI  :  

来源: DOAJ

【 摘 要 】

Huntington's disease (HD) is characterized by neuronal loss in the striatum, ultimately leading to an ‘imbalance’ in the electrical activity of the basal ganglia-thalamocortical circuits. To restore this ‘imbalance’ in HD patients, which is held responsible for (some) of the motor symptoms, different basal ganglia nuclei have been targeted for surgical therapies, such as ablative surgery and deep brain stimulation. However, evidence to target brain nuclei for surgical therapies in HD is lacking. We reasoned that a neuronal and metabolic mapping of the basal ganglia nuclei could identify a functional substrate for therapeutic interventions. Therefore, the aim of the present study was to investigate the metabolic and neuronal activity of basal ganglia nuclei in a transgenic rat model of HD (tgHD). Subjects were 10–12 month old tgHD rats and wildtype littermates. We examined the striatum, globus pallidus, entopeduncular nucleus, the subthalamic nucleus and substantia nigra at different levels. First, we determined the overall neuronal activity at a supracellular level, by cytochrome oxidase histochemistry. Secondly, we determined the subcellular metabolic activity, by immunohistochemistry for peroxisome proliferator-activated receptor-γ transcription co-activator (PGC-1α), a key player in the mitochondrial machinery. Finally, we performed extracellular single unit recordings in the nuclei to determine the cellular activity. In tgHD rats, optical density analysis showed a significantly increased cytochrome oxidase levels in the globus pallidus and subthalamic nucleus when compared to controls. PGC-1α expression was only enhanced in the subthalamic nucleus and electrophysiological recordings revealed decreased firing frequency of the majority of the neurons in the globus pallidus and increased firing frequency of the majority of the neurons in the subthalamic nucleus. Altogether, our results suggest that the globus pallidus and subthalamic nucleus play a role in the neurobiology of HD and can be potential targets for therapeutic interventions.

【 授权许可】

Unknown