Human GABAA receptors on dopaminergic neurons in the pars compacta of the substantia nigra

Abstract

The γ-aminobutyric acid A (GABAA) receptor subunit expression of the dopaminergic cells of the substantia nigra (SN) was investigated in the present study. Especially the dopaminergic cells, located in the pars compacta of SN (SNc), are of great neurologic interest, because the functional deficit and depletion of these cells are the correlate of Parkinson's disease. We used a combination of in situ hybridization histochemistry (ISH) and immunohistochemistry (IHC) on sections of human postmortem mesencephalon to investigate the expression of GABAA receptor subunit messenger RNAs (mRNAs) and of the receptor protein in dopaminergic SN cells. Immunohistochemical detection of tyrosine hydroxylase (TH), the pivotal enzyme of dopamine synthesis, was used to define the boundaries of SN pars reticulata (SNr) and pars compacta subregions. In SNr, all neurons were labeled by subunit-specific oligonucleotide probes and the amount of GABAA receptor mRNA expression was quantified as α1 = β2 > γ2 > α3. In contrast, in SNc, only around 25% of neurons expressed mRNA transcripts of GABAA receptor subunits, quantified as α1 = β2 > γ2 > α3 > α4 = β3. In approximately the same percentage of neurons, which were labeled by α1-subunit-specific probe, the α1-subunit also was detected at the protein level by a specific monoclonal antibody. We, therefore, could demonstrate that a subset of dopaminergic neurons in human SNc receive inhibitory synaptic input by means of GABAA receptors mainly of the α1β2γ2 subtype. This might represent a negative feedback loop between the striatum and the SNc and be a target of pharmacologic interventions in neurodegenerative diseases such as Parkinson's disease. © 2002 Wiley-Liss, Inc.