The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum

Abstract

In an effort to determine subunit compositions of in vivo GABAA receptors, the cellular localization of 13 subunit encoding mRNAs (alpha 1-alpha 6, beta 1-beta 3, gamma 2-gamma 3, delta) was determined in the rat olfactory bulb and cerebellum. Cerebellar granule cells expressed significant quantities of alpha 1, alpha 6, beta 2, beta 3, gamma 2, and delta mRNAs. They contained very much lower levels of alpha 4, beta 1, and gamma 3 mRNAs, and the alpha 2, alpha 3, alpha 5, and gamma 1 genes appeared to be silent. Purkinje cells contained only the alpha 1, beta 2, beta 3, and gamma 2 mRNAs. Putative Bergmann glial cells were found to contain the gamma 1 mRNA and possibly the alpha 2 mRNA. In the molecular layer, only the alpha 1, beta 2 and gamma 2 mRNAs were expressed in stellate/basket cells. The alpha 3 probe hybridized weakly to targets in the molecular layer. The inferior olivary nucleus contained significant quantities of alpha 2, alpha 4, and gamma 1 transcripts, with the alpha 1, alpha 3, beta 2, beta 3, and gamma 2 mRNAs also present. In the olfactory bulb, mitral cells were found to express the alpha 1, beta 1, beta 2, beta 3, and gamma 2 mRNAs strongly and the alpha 3 mRNA weakly. Tufted cells contained alpha 1, alpha 3, beta 2, beta 3, and gamma 2 mRNAs and, occasionally, the alpha 2 mRNA. In the internal granule cells the alpha 2, alpha 4, alpha 5, beta 3, and delta mRNAs were all present. Low levels of alpha 3, gamma 1, gamma 2, and gamma 3 mRNAs were also noted in these cells. Periglomerular cells expressed low levels of alpha 2, alpha 3, alpha 4, beta 2, beta 3, gamma 1, gamma 2, and gamma 3 mRNAs. No alpha 6 mRNA was present in the olfactory bulb. Correlations that are general ones from other brain regions are the colocalizations of alpha 1 beta 2, alpha 2 beta 3, and alpha 4 delta mRNAs. In both the olfactory bulb and cerebellum, alpha 1 beta 2 gamma 2 receptor cores are probably employed. The delta-subunit mRNA appears to codistribute with alpha- subunit mRNAs (alpha 4 and alpha 6) associated with GABAA subunits that fail to bind benzodiazepine agonists.

Effect of the α subunit subtype on the macroscopic kinetic properties of recombinant GABAA receptors

“…While the αxβ3γ2L combination is not necessarily the most common native isoform for each of the α subtypes (McKernan and Whiting, 1996), it was selected to provide a standard background for comparison. The γ2 subunit is the most widely expressed of the γ subtypes, and β2/3 subtypes are more common than the β1 in most regions (Laurie et al, 1992a;Wisden et al, 1992). The β2 and β3 subunits have high structural homology and confer similar pharmacological properties (Smith et al, 2004).…”

“…Neuronal receptors are likely to be subject to modulation by post-translational modifications such as phosphorylation (Brandon et al, 2002), interactions with cytoskeletal proteins (Chen and Olsen, 2007), and differences in assembly and membrane targeting (Fritschy et al, 1998;Brünig et al, 2002;Klausberger et al, 2002). However, virtually all neurons and neuronal cell lines that express GABARs produce multiple subunit subtypes (Wisden et al, 1992;Laurie et al, 1992a;Tyndale et al, 1994;Neelands et al, 1998) and neuronal populations which express only one or two of the α subtypes are extremely rare. Therefore, in order to control the subunit composition of the receptors and describe the characteristics of a homogeneous population of receptors, these studies must be done in cell lines that do not normally express functional GABARs.…”

“…The α subtypes show relatively high structural homology (60-80%) but confer distinct functional and pharmacological properties (Mehta and Ticku, 1999;Korpi et al, 2002). The mRNA for each of the α subtypes exhibits a unique distribution pattern throughout the rat brain, and is differently regulated throughout development (Laurie et al, 1992a(Laurie et al, , 1992bWisden et al, 1992). GABARs produced by neurons in different brain regions and at different stages of development could therefore have very different characteristics due to variations in subunit composition.…”

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…The restricted anatomical localization of the a 6 , a 4 , and d-GABA A receptor subunits (Gutierrez et al, 1996;Laurie et al, 1992;Peng et al, 2002), and these combinations contributing less than 5% of the total GABA A receptor pool (Hanchar et al, 2004), likely explains the limited effects removal of the subunits associated with the BZD-insensitive receptors have on function. Nonetheless, definition of specific brain regions influenced by an action of ethanol on these BZD-insensitive receptors, which could support selected functions associated with the GABAmimetic profile of ethanol, remains an open issue.…”

Normal formation of the postsynaptic elements of GABAergic synapses in the reeler cerebellum

“…In the cerebellum, granule cells express the GABA A receptor α1 and α6 subunit mRNAs and the subunit proteins are targeted to the GABAergic synaptic site in the synaptic glomeruli [28,47,69]. Purkinje cells, on the other hand, express only the α1 subunit but not remaining five α subunits and its protein is trafficked to the dendritic shafts and cell bodies opposite the GABAergic terminals.…”