Distribution of α1, α4, γ2, and δ subunits of GABAA receptors in hippocampal granule cells

Abstract

GABA A receptors are pentamers composed of subunits derived from the α, β, γ, δ, θ, ε, and π gene families. α1, α4, γ2, and δ subunits are expressed in the dentate gyrus of the hippocampus, but their subcellular distribution has not been described. Hippocampal sections were double-labeled for the α1, α4, γ2, and δ subunits and GAD65 or gephyrin, and their subcellular distribution on dentate granule cells was studied by means of confocal laser scanning microscopy (CLSM). The synaptic versus extrasynaptic localization of these subunits was inferred by quantitative analysis of the frequency of colocalization of various subunits with synaptic markers in high-resolution images. GAD65 immunoreactive clusters colocalized with 26.24±0.86% of the α1 subunit immunoreactive clusters and 32.35±1.49% of the γ2 subunit clusters. In contrast, only 1.58±0.13% of the α4 subunit immunoreactive clusters and 1.92±0.15% of the δ subunit clusters colocalized with the presynaptic marker GAD65. These findings were confirmed by studying colocalization with immunoreactivity of a postsynaptic marker, gephyrin, which colocalized with 27.61±0.16% of the α1 subunit immunoreactive clusters and 23.45±0.32% of the γ2 subunit immunoreactive clusters. In contrast, only 1.90±0.13% of the α4 subunit immunoreactive clusters and 1.76±0.10% of the δ subunit clusters colocalized with gephyrin. These studies demonstrate that a subset of α1 and γ2 subunit clusters colocalize with synaptic markers in hippocampal dentate granule cells. Furthermore, all four subunits, α1, α4, γ2, and δ, are present in the extrasynaptic locations.

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

“…The subunit composition determines the pharmacological properties of GABA A R. Drugs, including neurosteroids, which interact with the receptors, can affect the subunit mRNA expression (Sun et al, 2004). GABA A R usually contains two a-subunits, two b-subunits, and either a g or d-subunit, with the d-subunit being rare (Sun et al, 2004).…”

“…The subunit composition determines the pharmacological properties of GABA A R. Drugs, including neurosteroids, which interact with the receptors, can affect the subunit mRNA expression (Sun et al, 2004). GABA A R usually contains two a-subunits, two b-subunits, and either a g or d-subunit, with the d-subunit being rare (Sun et al, 2004). GABA A Rs containing a d-subunit, rather than a g-subunit, are more sensitive to neurosteroids (Belelli et al, 2002), and mice lacking GABA A d-subunits are less sensitive to neurosteroids (Brown et al, 2002;Mihalek et al, 1999Mihalek et al, , 2001Stell et al, 2003;Wohlfarth et al, 2002).…”

Silencing Hyper-Excitable Neurons as a Treatment for Status Epilepticus and Temporal Lobe Epilepsy.

“…GABA A receptors are composed of six α subunits, four β subunits, three types of γ subunits and one of each δ, θ, ε and π subunits (Macdonald and Botzolakis 2009).GABRA4 is the human promoter for the α4 subunit (Roberts, Raol et al 2005). The dentate granule cells in the hippocampus show high expression of α4 GABA A subunit receptors (Sun, Sieghart et al 2004). Studies have shown that α4 subunit expression increases in the dentate gyrus of epileptic rats .…”

“…In order to package all our chosen genes within that size limit, promoters are required which are both small and neuronal-specific. GABRA4 is the human promoter of GABA A α4 receptors (Sun, Sieghart et al 2004). …”

“…The dentate granule cells in the hippocampus express GABA A α4 receptors (Sun, Sieghart et al 2004). The expression of GABA A α4 receptors have been found to increase in the dentate gyrus of rat model of temporal lobe epilepsy as well as in TLE humans (BrooksKayal, Shumate et al 1998).…”