gms | German Medical Science

Objective: Deep brain stimulation (DBS) modulates the expression of immediate early genes and of genes involved in neurotransmission suggesting down-stream molecular alterations. To our knowledge, no experimental work has been published reporting the effect on gene-expression in distinct brain areas of awake, parkinsonian rats receiving long-term DBS.

Methods: We utilized chronic stimulation (24 h) of the subthalamic nucleus (STN) in rats rendered parkinsonian by stereotactic bilateral 6-hydroxy-dopamine lesions in the substantia nigra (pars compacta). Rats sham-lesioned with saline served as controls. Phenotype as well as possible stimulation effects were assessed behaviourally using a video-based tracking system. Stimulation was applied to only one of the bilaterally implanted electrodes, thus, the non-stimulated hemisphere of the same animal could serve as an internal control. Following STN stimulation, RNA was isolated from the sensorimotor cortex and the striatum of both hemispheres. Gene expression was studied by microarray analysis (Affymetrix GeneChip^® Rat Genome 230 2.0).

Results: Behavioural analysis of parkinsonian vs. control rats showed a significant decrease of quantitative locomotion parameters following lesioning (total distance, locomotion time, and mean velocity) reflecting hypo- and bradykinetic aspects of locomotion in Parkinson’s disease. A mild but non-significant improvement of hypokinetic parameters could be observed during unilateral STN-stimulation. Microarray analysis revealed an increase in the expression of numerous genes in the sensorimotor cortex of parkinsonian as well as sham-lesioned rats following DBS. In contrast, no such upregulation was observed in the striatum where the majority of genes altered by DBS were down-regulated. We are currently validating the data for individual genes by quantitative RT-PCR.

Conclusions: Our data suggest that DBS induces complex changes in gene expression in different brain structures of the cortico-basal ganglia-thalamic loop. The study of such molecular alterations may contribute to our understanding of the well-known but hitherto inexplicable long-term effects of DBS, in particular the delayed amelioration of akinesia in Parkinson’s disease.