GABA(A) receptor characterization and subunit localization in the human sub-ventricular zone

Abstract

It is now well established that the human brain continuously produces new stem cells until well into old age. One of these stem-cell rich areas in the human brain is the sub-ventricular zone (SVZ). The human SVZ is organized in four distinctive layers containing type A, B and C cells. To date, no studies have investigated the distribution of inhibitory neurotransmitters such as γ-aminobutyric acid (GABA) and their respective receptors on the different cell types in the human SVZ. GABA(A) receptors (GABA(A)R) are ubiquitously expressed, inhibitory heteropentameric chloride ion channels comprised of a variety of subunits that are targeted by many prescribed drugs. In this study we present detailed immunohistochemical data on the regional and cellular localization of α₁, α₂, α3, β₂,₃ and γ₂ subunits of GABA(A)R in the human SVZ. The results from our double and triple labeling studies demonstrate that the cell types and subunit composition throughout the SVZ is heterogeneous; the thickness of the SVZ and GABA(A)R α₂ and γ₂ expression is increased especially in the vicinity of large SVZ blood vessels. GABA(A)R γ₂ is the most specific to the SVZ and present on various cells that express, either glial fibrillary acidic protein (GFAPδ) or polysialic acid-neural cell adhesion molecule (PSA-NCAM) separately, or together in a respective ratio of 7:6:2. Proliferating (type C) cells in the SVZ express GAD65/67, GFAPδ and GABA(A)R β₂,₃ receptor subunits. Within the SVZ the majority of cells have an unexpected nuclear GABA(A)R β₂,₃ expression that is inversely proportional to that of PCNA (proliferating cell nuclear antigen marker), which is a very different pattern of expression compared with underlying caudate nucleus cells. Taken together our results provide a detailed description of the chemo-architecture of the adult human SVZ demonstrating the importance of GABA and GABA(A) receptors on the various cell types in the SVZ.

Keywords: GABA; GABA(A) receptor; Human brain; Progenitor cell; Subventricular zone.