Differential localization of GABA_A receptor subunits within the substantia nigra of the human brain: An immunohistochemical study

Abstract

Gamma-aminobutyric acid(A) (GABA(A)) receptors (GABA(A)R) are inhibitory heteropentameric chloride ion channels comprising a variety of subunits and are localized at postsynaptic sites within the central nervous system. In this study we present the first detailed immunohistochemical investigation on the regional, cellular, and subcellular localisation of alpha(1), alpha(2), alpha(3), beta(2,3), and gamma(2) subunits of the GABA(A)R in the human substantia nigra (SN). The SN comprises two major regions, the SN pars compacta (SNc) consisting of dopaminergic projection neurons, and the SN pars reticulata (SNr) consisting of GABAergic parvalbumin-positive projection neurons. The results of our single- and double-labeling studies demonstrate that in the SNr GABA(A) receptors contain alpha(1), alpha(3), beta(2,3), and gamma(2) subunits and are localized in a weblike network over the cell soma, dendrites, and spines of SNr parvalbumin-positive nonpigmented neurons. By contrast, GABA(A)Rs on the SNc dopaminergic pigmented neurons contain predominantly alpha(3) and gamma(2) subunits; however there is GABA(A)R heterogeneity in the SNc, with a small subpopulation (6.5%) of pigmented SNc neurons additionally containing alpha(1) and beta(2,3) GABA(A)R subunits. Also, in the SNr, parvalbumin-positive terminals are adjacent to GABA(A)R on the soma and proximal dendrites of SNr neurons, whereas linear arrangements of substance P-positive terminals are adjacent to GABA(A) receptors on all regions of the dendritic tree. These results show marked GABA(A)R subunit hetereogeneity in the SN, suggesting that GABA exerts quite different effects on pars compacta and pars reticulata neurons in the human SN via GABA(A) receptors of different subunit configurations.

Probing GABA Receptor Function in Schizophrenia with Iomazenil

“…Converging lines of evidence suggest that the activity of DA neurons in the VTA is under tonic inhibitory control by GABA-A receptors (Fritschy and Mohler, 1995;Pirker et al, 2000;Waldvogel et al, 2008). Specifically relevant to this study, systemic administration of GABA-A receptor inverse agonist, FG7142 has been shown to activate VTA neurons (Murphy et al, 1996).…”

Enhancement of GABAergic Activity: Neuropharmacological Effects of Benzodiazepines and Therapeutic Use in Anesthesiology

“…In temporal neocortex, ␣2 expression is strongest in layers II and III (Loup et al, 2006) and in layers II, IV, and V in motor cortex (Petri et al, 2003). No ␣2 expression was detected in the substantia nigra (Waldvogel et al, 2008). In hu- 246 man hippocampus, the ␣2 subunit is very abundant throughout the hippocampal formation, the expression being strongest in dentate molecular layer (Loup et al, 1998(Loup et al, , 2000.…”

“…The GABA A R system is highly conserved in mammals, but some quantitative and/or qualitative differences have been found between human and rat in brain regional expression patterns of the subunits. The expression of some subunits is very restricted; e.g., the expression of ␣6 subunit is confined to cerebellar granule cells (Hadingham et al, 1996), whereas ␣1 is widely expressed in most brain regions (Houser et al, 1988;Akbarian et al, 1995;Loup et al, 2006;Waldvogel et al, 2008;Fatemi et al, 2009). Some cell types express only a small repertoire of subunit mRNAs (e.g., ␣1, ␤2, ␤3 and ␥2 in cerebellar Purkinje cells) (Wisden et al, 1992), whereas the majority of individual human dentate granule neurons express 10 or more different subunit mRNAs (Brooks-Kayal et al, 1999).…”

“…The expression of ␣1 is strongest in motor cortex layers III and IV (Petri et al, 2003). In human substantia nigra pars reticulata, ␣1 subunit is expressed at comparatively high levels, whereas in substantia nigra pars compacta, the expression is very low (Waldvogel et al, 2008). In human hippocampus, the expression of ␣1 is highest in the molecular layer of the dentate gyrus and cornu ammonis (CA) 1, moderate in CA2, and nearly devoid in CA3 region (Houser et al, 1988;Loup et al, 2000;Pirker et al, 2003;Rissman et al, 2003Rissman et al, , 2004.…”

“…The expression of ␣3 is strongest in motor cortex layers IV to VI (Petri et al, 2003). ␣3 subunit is expressed at relatively high levels in substantia nigra pars compacta and pars reticulata (Waldvogel et al, 2008). Although virtually absent in the rat hippocampus (Fritschy and Mohler, 1995), in human hippocampus ␣3 subunit is very intense in CA1, subiculum, and the dentate molecular layer (Loup et al, 1998(Loup et al, , 2000Pirker et al, 2003).…”