The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development

Abstract

The embryonic and postnatal expression of 13 GABAA receptor subunit genes in the rat CNS was studied by in situ hybridization. Each transcript exhibited a unique regional and temporal developmental expression profile. For example, in both embryonic and early postnatal cortex and thalamus, expression of the alpha 2, alpha 3, alpha 5, and beta 3 mRNAs was pronounced. In particular, the alpha 5 gene expression underwent a prominent peak in early brain. Subsequently, the thalamocortical expression of these four genes substantially diminished and was superseded in the adult by the alpha 1, alpha 4, beta 2, and delta subunit mRNAs. Similarly, gamma 1 and gamma 3 gene expression also dropped markedly during development, their initial stronger expression being restricted to relatively few structures. In contrast, gamma 2 gene expression was widespread and mostly remained constant with increasing age. The medial septum and globus pallidus were regions expressing few subunits in both early postnatal and adult stages, allowing clear developmental combinatorial changes to be inferred (alpha 2/alpha 3 beta 2 gamma 2 to alpha 1 beta 2 gamma 2, alpha 2/alpha 3 beta 2 gamma 1 to alpha 1 beta 2 gamma 1/gamma 2, respectively). In contrast, cerebellar Purkinje cells exhibited no developmental switch, expressing only the alpha 1, beta 2, beta 3, and gamma 2 mRNAs from birth to adult. Certain GABAA transcripts were also detected in germinal zones (e.g., beta 1, beta 3, gamma 1) and in embryonic peripheral tissues such as dorsal root ganglia (e.g., alpha 2, alpha 3, beta 3, gamma 2) and intestine (gamma 3). Some parallels in regional and temporal CNS expression were noted (e.g., alpha 1 beta 2, alpha 2 beta 3, alpha 4/alpha 6 delta), whereas the alpha 5 and beta 1 regional mRNA expressions converted over time. The changes of GABAA receptor subunit gene expression suggest a molecular explanation for earlier observations on changing ligand binding affinities. Thus, the composition, and presumably properties, of embryonic/early postnatal rat GABAA receptors differs markedly from those expressed in the adult brain.

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

“…The β2 and β3 subunits have high structural homology and confer similar pharmacological properties (Smith et al, 2004). The β3 is more highly expressed in the developing brain, while the β2 predominates in the adult brain (Laurie et al, 1992b). Many previous studies have used the β3 subunit, so we selected this subtype to allow a more direct comparison to earlier findings.…”

“…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.…”

Extrasynaptic localization of GABA in the developing mouse cerebellum

“…Furthermore, we performed double staining with calbindin, which is a marker protein of Purkinje cells (Yamakuni et al, 1984), or the GABA A receptor α1 subunit, which is an essential component of the GABA A receptors at the GABAergic synapses in mature cerebellar neurons (Laurie et al, 1992;Merlo et al, 2000;Takayama and Inoue, 2003).…”

“…The GABAergic synapses were detected by immunohistochemistry for the GABA A receptor α1 subunit since the α1 subunit is considered to be an essential subunit for inhibitory synaptic transmission in the matured cerebellar cortex. The α1 subunit is the most dominant α subunit in all types of mature cerebellar neurons, and appears when and where GABAergic synapses are formed (Laurie et al, 1992;Merlo et al, 2000;Takayama and Inoue, 2003;Takayama and Inoue, 2004b).…”

Expression of GABAA receptor subunit mRNAs in hippocampal pyramidal and granular neurons in the kindling model of epileptogenesis: an in situ hybridization study

“…By altering the expression pattern of GABAAR subunit encoding genes, neurons may have the ability to fine tune their GABAergic signal transduction pathway in response to changing conditions. Changes in subunit expression profile during development [30] and in response to transient cerebral ischemia [33], chronic GABAA/benzodiazepine receptor agonists/antagonists [15,25,42,56,63,80] or ethanol treatment [41,44,49] may underly functional changes of GABAARS. Modified GABAAR subunit mRNA levels were also described in rats that were subjected to repeated electrical stimulations with short interstimulus intervals resuiting in recurrent epileptiform seizures (rapid kindling procedure) [27].…”