Abstract
High-frequency stimulation of the subthalamic nucleus (STN-HFS) is widely used as therapeutic intervention in patients suffering from advanced Parkinson’s disease. STN-HFS exerts a powerful modulatory effect on cortical motor control by orthodromic modulation of basal ganglia outflow and via antidromic activation of corticofugal fibers. However, STN-HFS-induced changes of the sensorimotor cortex are hitherto unexplored. To address this question at a genomic level, we performed mRNA expression analyses using Affymetrix microarray gene chips and real-time RT-PCR in sensorimotor cortex of parkinsonian and control rats following STN-HFS. Experimental parkinsonism was induced in Brown Norway rats by bilateral nigral injections of 6-hydroxydopamine and was assessed histologically, behaviorally, and electrophysiologically. We applied prolonged (23h) unilateral STN-HFS in awake and freely moving animals, with the non-stimulated hemisphere serving as an internal control for gene expression analyses. Gene enrichment analysis revealed strongest regulation in major histocompatibility complex (MHC) related genes. STN-HFS led to a cortical downregulation of several MHC class II (RT1-Da, Db1, Ba, and Cd74) and MHC class I (RT1CE) encoding genes. The same set of genes showed increased expression levels in a comparison addressing the effect of 6-hydroxydopamine lesioning. Hence, our data suggest the possible association of altered microglial activity and synaptic transmission by STN-HFS within the sensorimotor cortex of 6-hydroxydopamine treated rats.
Highlights
In Parkinsons disease (PD), nigrostriatal dopamine depletion is the source of severe disturbances within skeletomotor loops that tightly link cortex, basal ganglia and thalamus [1,2]
Microelectrode-guided targeting of the subthalamic nucleus (STN) led to a high rate of successfully implanted STN-HFS electrodes in rats used for gene expression profiling (n = 6; for a typical electrode trajectory, see Figure 2A)
As the threshold for inducing typical dyskinetic movements in this animal did not differ from the group average, it was still included in confirmatory RT-PCR validation
Summary
In Parkinsons disease (PD), nigrostriatal dopamine depletion is the source of severe disturbances within skeletomotor loops that tightly link cortex, basal ganglia and thalamus [1,2]. Return to baseline symptom severity is variable after HFS-offset [6] Such latency differences and carry-over effects suggest that in addition to immediate electrophysiological or neurochemical modulation of neuronal activity, HFS leads to adaptive and plastic changes on a longer time-scale. This view is supported by experimental evidence that STN-HFS induces synaptic plasticity in the rat STN [7] and mediates neuroprotection on substantia nigra dopaminergic neurons in a model of neurotoxin-induced degeneration [8,9]
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