Brain Advance Access originally published online on December 4, 2006
Brain 2007 130(1):265-275; doi:10.1093/brain/awl337
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Metabolic activity of cerebellar and basal ganglia-thalamic neurons is reduced in parkinsonism
1 INSERM, UMR679, Neurology and Experimental Therapeutics Paris, France 2 Pierre and Marie Curie University-Paris, Faculty of Medicine Paris, France 3 Salpetriere Hospital Paris, France 4 Experimental Neurology and Neurosurgery, Department of Human Anatomy and Psychobiology, School of Medicine, University of Murcia Campus de Espinardo, Murcia, Spain
Correspondence to: C. François, INSERM UMR679, Hôpital de la Salpetrière, 47 Bd de l'Hôpital, 75013 Paris, France Email: cfrancoi{at}ccr.jussieu.fr
We have examined whether degeneration of nigrostriatal dopaminergic neurons causes dysfunction of both the basal ganglia-thalamic and cerebello-thalamic pathways. Changes in the activity of thalamic neurons receiving input from the basal ganglia or the cerebellum were examined in two models of Parkinson's disease, 6-hydroxydopamine (6-OHDA)-lesioned rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys. Metabolic activity of the neurons was evaluated at the cellular level by quantitative in situ hybridization, using the expression of messenger RNA for subunit I of cytochrome oxidase (COI), encoded by the mitochondrial genome, as the marker. COI mRNA expression decreased significantly in thalamocortical neurons receiving input from the substantia nigra (–50.6%) or the cerebellum (–45%) in 6-OHDA-lesioned rats compared with controls. The decrease was observed in all thalamic neurons whether or not they were retrogradely labelled with a tracer injected into the motor cortex. Similarly, COI mRNA expression decreased in projection neurons and interneurons of the thalamus receiving input from the substantia nigra (–39 and –38%, respectively), the internal pallidum (–20 and –42.4%, respectively) and the cerebellum (–36.2 and –50%, respectively) of MPTP-treated monkeys compared with controls. These decreases in COI mRNA levels show that nigrostriatal denervation results in a decrease in the metabolic activity of thalamic neurons in the territories innervated by the substantia nigra, pallidum and cerebellum, which in turn is indicative of a decrease in their neuronal activity. The decrease did not concern the entire thalamus, however, since metabolic activity was unchanged in two thalamic nuclei considered to be limbic structures, the laterodorsal nucleus in 6-OHDA-lesioned rats and the anterior nucleus in MPTP-treated monkeys. Hypoactivity of both the basal ganglia-thalamic and cerebellar-thalamic pathways might therefore be implicated in the development of parkinsonian symptoms.
Key Words: Parkinson's disease; thalamus; metabolic activity; cytochrome oxidase; non-human primates
Abbreviations: COI, subunit I of cytochrome oxidase; DAT, dopamine transporter; GAD, glutamic acid decarboxylase; 6-OHDA, 6-hydroxydopamine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; TH, tyrosine hydroxylase; WGA-HRP, wheat germ agglutinin conjugated to horseradish peroxidase
Received June 26, 2006. Revised October 3, 2006. Accepted November 6, 2006.