Effects of L-DOPA on Gene Expression in the Frontal Cortex of Rats with Unilateral Lesions of Midbrain Dopaminergic Neurons

Abstract

The development of Parkinson's disease (PD) causes dysfunction of the frontal cortex, which contributes to the hallmark motor symptoms and is regarded as one of the primary causes of the affective and cognitive impairments observed in PD. Treatment with L-DOPA alleviates motor symptoms but has mixed efficacy in restoring normal cognitive functions, which is further complicated by the psychoactive effects of the drug. We investigated how L-DOPA affects gene expression in the frontal cortex in an animal model of unilateral PD. We performed RNASeq analysis of gene expression in the frontal cortex of rats with 6-hydroxydopamine (6-OHDA)-induced unilateral dopaminergic lesions treated with L-3,4-dihydroxyphenylalanine (L-DOPA), for 2 weeks. The analysis of variance identified 48 genes with a significantly altered transcript abundance after L-DOPA treatment. We also performed a weighted gene coexpression network analysis (WGCNA), which resulted in the detection of 5 modules consisting of genes with similar expression patterns. The analyses led to three primary observations. First, the changes in gene expression induced by L-DOPA were bilateral, although only one hemisphere was lesioned. Second, the changes were not restricted to neurons but also appeared to affect immune or endothelial cells. Finally, comparisons with databases of drug-induced gene expression signatures revealed multiple nonspecific effects, indicating that a part of the observed response is a common pattern activated by multiple types of drugs in different target tissues. Taken together, our results identify cellular mechanisms in the frontal cortex that are involved in the response to L-DOPA treatment. 4 Significance statement The development of Parkinson's disease (PD) causes dysfunction of the frontal cortex, which contributes to the motor and cognitive impairments observed in PD. L-DOPA improves motor symptoms but has mixed efficacy in restoring normal cognitive functions. We investigated how L-DOPA affects gene expression in the frontal cortex in an animal model of unilateral PD. We identified 48 genes with L-DOPA-altered expression levels and gene clusters that follow similar drug-evoked expression patterns. Our findings suggest that the response to L-DOPA was bilateral, involved distinct cell types and overlapped with expression changes evoked by drugs of multiple classes in different tissues. Overall, our results identify cellular mechanisms in the frontal cortex that are involved in the response to L-DOPA treatment.

Translational profiling reveals novel gene expression changes in the direct and indirect pathways in a mouse model of LDOPA-induced dyskinesia

“…Indeed, the TRAP-RNAseq model has led to the discovery of previously unknown distinct MSN subpopulations involved in locomotor control (Fieblinger, 2021). Third, while our study focused on changes in gene expression in the striatum, other studies have demonstrated that chronic LDOPA can induce changes in gene expression in other areas of the brain such as the frontal cortex, as well as in cell types other than MSNs, including immune and endothelial cells (Radlicka et al, 2021). Lastly, our study did not consider changes in DNA methylation which have been implicated in the development and maintenance of LID (Figge et al, 2016).…”