Adaptive gene expression changes on the healthy side of parkinsonian rats

Abstract

Parkinson’s disease (PD) is an asymmetric neurodegenerative disorder, and secondary adaptive mechanisms of the less-affected side could potentially compensate for parkinsonian symptoms. Here, we analyzed gene expression changes on the healthy side of a unilateral PD rat model and correlated these changes with locomotor velocity, which is known to be decreased in PD. Four weeks after a unilateral 6-hydroxydopamine lesion, the spontaneous locomotor velocity of rats was recorded just prior to brain extraction. We then analyzed the gene expression levels of markers of the direct (dynorphin and D1-class dopamine receptors) and indirect (enkephalin and D2-class dopamine receptors) pathways in the contralateral healthy striatum by in situ hybridization histochemistry. In addition, we analyzed the expression of several striatal and cortical glutamatergic markers, as well as nigral tyrosine hydroxylase (TH) and nigral dopamine transporter (DAT). We found a significant positive correlation between the mRNA expression levels of contralateral D1-class dopamine receptors and the mean locomotor velocity, at 4 weeks after surgery in parkinsonian rats but not in controls. Moreover, we observed a significant increase in the level of dynorphin mRNA in the lateral part of the contralateral striatum of parkinsonian rats compared to the controls. In contrast, no contralateral changes were observed in the striatal indirect pathway. We also did not find any significant contralateral modifications of TH, DAT or glutamatergic markers in PD animals, indicating that changes in direct pathway genes are not due to nigrostriatal dopaminergic or corticostriatal glutamatergic innervation. In conclusion, our results suggest a role of the healthy striatal direct pathway in counteracting dopaminergic denervation effects on motor symptoms.