gms | German Medical Science

Objective: Changes in neuronal activity are thought to underlie the development of symptoms in neurodegenerative diseases such as Parkinson's disease (PD). Adaptive neuronal responses to therapeutic interventions such as deep brain stimulation (DBS), assessed on the level of gene expression changes might contribute to our understanding of its long-term effects.

Methods: We investigated global changes in gene expression in key structures of the cortico-basal ganglia-thalamic loop, i.e. sensorimotor cortex (CXM) and striatum (STR). PD- and control-rats received long-term DBS of the subthalamic nucleus (STN) and microarray techniques and real-time RT-PCR were utilized for gene expression analysis. Rats were rendered parkinsonian through bilateral infusion of 6-Hydroxydopamine (6-OHDA) into the substantia nigra (SN). Spontaneous motor activity was assessed using a video-based tracking system. Local field potentials (LFP) were recorded from frontal cortex under resting conditions to analyze neuronal population oscillations. Unilateral STN-DBS was applied in awake and freely moving animals for 23 hrs, with the non-stimulated hemisphere serving as an internal control for gene expression analysis.

Results: STN-DBS primarily lead to an upregulation of gene expression in CXM (98 of 116 genes, 85%) and downregulation in STR (97 of 105, 92%) of PD rats, with ca. 20% differential overlap between the two structures. Notably, the effects of the 6-OHDA-lesion primarily resulted in the downregulation of gene expression in CXM and STR of the non-stimulated hemispheres of PD compared to control rats. Interestingly, 39 cortical genes (33%) exhibited a differential overlap between the effects of lesion and DBS. Among those, a significantly overrepresented group was found with immunity-related MHC class II genes, H2-Ea and CD74 showed the largest fold changes in particular. MHC II genes were upregulated following lesion and downregulated following DBS, while the remaining bulk of differential overlap showed the opposite regulation pattern. Microarray data was validated for H2-Ea and CD-74 using RT-PCR.

Conclusions: The expression of MHC I/II genes has recently been described in non-immunity-related contexts, in particular regarding long-term plasticity of excitatory synaptic transmission. Here, we present data showing DBS-specific trans-synaptic downregulation of MHC II genes. We hypothesize that this downregulation reflects the DBS-mediated liberation of sensorimotor cortex from pathologically entrained oscillatory activity.