Neuropathology in the dorsolateral prefrontal cortex in Parkinson's disease

Abstract

Degeneration of dopaminergic neurons in the substantia nigra pars compacta is the hallmark neuropathological feature of Parkinson's disease (PD). Multiple lines of evidence from anatomical and imaging studies indicate that cell loss or cell dysfunction also occur in other brain regions. The dorsolateral prefrontal cortex (DLPFC) is a region of interest because it could be implicated in both cognitive and motor symptoms of PD. However, studies in this brain region are limited and the extent of pathology is unclear. Work in this thesis was aimed at identifying possible neuropathology in post-mortem PD tissue from Brodmann area 9 (BA9), a region of the DLPFC. In the first study, using design-based stereology and radioisotopic in situ hybridization histochemistry (ISHH), we found that expression of two mitochondrial genes, NDUFS1 and COX1, was not altered and that no global loss of neurons occurs in BA9 in PD. In a second study, using ISHH and gene expression microarray analysis (One-Color Agilent 60-mer Whole Human Genome Microarray), we found decreased gene expression of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67) in BA9 in PD, an effect that was not paralleled by a decrease in the numbers of GAD67 mRNA-expressing neurons. In a third study, using ISHH, we found that gene expression of the calcium-binding protein parvalbumin, which is selectively expressed in a subset of cortical GABAergic interneurons, is decreased in BA9 in PD. However, we found no loss of immunolabeled parvalbumin-positive neurons in BA9 in PD. In summary, the results indicate that expression of two key markers of GABAergic activity, GAD67 and parvalbumin, is depressed in BA9 in PD and that these effects are not due to a loss of neurons. This suggests that GABAergic neurotransmission is deficient in the DLPFC in PD and we propose that treatments aimed at restoring GABAergic inhibition in BA9 would have therapeutic efficacy in the symptomatic treatment of PD.