The Pharmacology of Extrasynaptic GABAA Receptors

GABA receptor subunit distribution and FMRP–mGluR5 signaling abnormalities in the cerebellum of subjects with schizophrenia, mood disorders, and autism

“…There are 19 different GABA A receptor subunits: alpha 1–6 (α1–6), beta 1–3 (β1–3), gamma1–3 (γ1–3), delta (δ), epsilon (ε), pi (π), theta (θ), and rho 1–3 (ρ1–3) that combine to form the various GABA A receptors (Brandon et al, 2000; Ma et al, 2005). These receptors are either mostly synaptic/postsynaptic (α1–4, β1–3, γ1–3, δ, ε, θ, π, ρ1–3), predominantly extrasynaptic (α4, α5, α6, and δ), or both (α5, ρ1) (Errington, 2014; Wafford, 2014). GABA A receptors are binding sites for benzodiazepines, steroids, and anesthetics, thus mediating their effects.…”

“…Interestingly, extrasynaptic GABA A receptors can be modulated both directly and indirectly by GABA B , serotonin, dopamine, noradrenalin, and metabotropic glutamate receptors (Errington, 2014). Additionally, synaptic GABA A receptors are composed of α1, α2, and α3 subunits along with β1–3, and γ2 subunits, while extrasynaptic receptors are composed of α1, α4, α5, β, γ2 and δ subunits (Farrar et al, 1999; Wafford, 2014). GABA B receptors are heterodimeric receptors consisting of one GABA B receptor 1 subunit (GABBR1) and one GABA B receptor 2 subunit (GABBR2).…”

“…The GABRα5 gene (GABRA5) is localized to 15q11.2-q13 (Knoll et al, 1992) and is considered one of the extrasynaptic GABA A receptors involved in tonic inhibitory neurotransmission (Wafford, 2014). mRNA for GABRα5 is expressed in the hippocampus, olfactory bulb, and hypothalamus in rat brain (Laurie et al, 1992; Wisden et al, 1992) as well as amygdala (Martin and Huntsman, 2014).…”

“…Mice that display reduced GABRα5 in the hippocampus also show deficits in latent inhibition (Gerdjikov et al, 2008), further implicating this subunit in cognition. Additionally, because of the importance of this receptor in cognition, it has also been a focus of therapeutic intervention for both Alzheimer’s disease and schizophrenia (Wafford, 2014). …”

“…GABRA6, the gene that codes for GABRα6 subunit, is located at 5q31.1-q35 (Hicks et al, 1994) and is another member of the extrasynaptic GABA A receptors (Wafford, 2014). GABRα6 mRNA has been found to localize exclusively to cerebellar granule neurons in rat brain (Laurie et al, 1992; Wisden et al, 1992).…”