1 Department of Clinical Neurobiology, University of Heidelberg, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany 2Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK
Abstract: g-Aminobutyric acid type A (GABAA) receptors, the major inhibitory neurotransmitter receptors responsible for fast inhibition in the basal ganglia, belong to the superfamily of "cys-cys loop'' ligand-gated ion channels. GABAA receptors form as pentameric assemblies of subunits, with a central Cl permeable pore. On binding of two GABA molecules to the extracellular receptor domain, a conformational change is induced in the oligomer and Cl", in most adult neurons, moves into the cell leading to an inhibitory hyperpolarization. Nineteen mammalian subunit genes have been identified, each showing distinct regional and cell-type-specific expression. The combinatorial assembly of the subunits generates considerable functional diversity. Here we place the focus on GABAA receptor expression in the basal ganglia: striatum, globus pallidus, substantia nigra and subthalamic nucleus, where, in addition to the standard a1p2/3g2 receptor subtype, significant levels of other subunits (a2, a3, a4, g1, g3 and 8) are expressed in some nuclei.
Keywords: GABA; GABAA receptor; basal ganglia; striatum; globus pallidus; substantia nigra; benzodiazepines
GABAA receptors are essential for the function of the entire basal ganglia network, providing fast (millisecond) synaptic as well as tonic extrasynaptic inhibition within and between the various basal ganglia nuclei (reviewed in Smith et al., 1998; Misgeld, 2004; Tepper and Bolam, 2004). As for other brain regions, different neuronal subtypes within the basal ganglia employ different GABAA receptor subtypes. Here we first review the genetics and structure of GABAA receptor subtypes; we then consider key drugs that act on the receptors to enhance or decrease GABAs actions; finally, we summarize which receptor subunit combinations are expressed in the various nuclei of the basal ganglia.
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GABAA receptors are GABA-gated anion channels responsible (together with ligand-gated glycine receptors) for most fast inhibitory synaptic transmission in the vertebrate central nervous system. GABAA receptors are permeable to HCO" and Cl" ions; the permeability ratio of HCO"/Cl" is approximately 0.2 to 0.4 (reviewed in Kaila et al., 1997). HCO" moves out of the cell causing a mild depolarization (the reversal potential for HCO" is — 12mV). In mature neurons Cl" usually moves into the cell overriding this mild depolarization, causing a strong inhibitory hyperpolarization, as the Cl" reversal potential is 15-20 mV more negative than the resting membrane potential. The Cl" gradient is maintained by K-Cl co-transporters (Rivera et al., 2005). Depending on the intracellular Cl" concentration, GABAA receptor activation can also lead to Cl" efflux and depolarization. This is the case, for example, during embryonic and early postnatal development when K-Cl co-transporters are not expressed at sufficient levels to efficiently transport Cl" out of the cell (Rivera et al., 2005). There are interesting caveats: adult dopaminergic neurons in the substantia nigra pars compacta have little KCC2 expression (Gulasci et al., 2003), possibly explaining the relatively low efficacy of GABAa receptor-mediated inhibition in nigral dopaminergic neurons (Gulasci et al., 2003). Further, KCC2 expression can vary in subdomains of neurons, thus affecting local Cl" gradients. KCC2 is absent from the axon initial segments of neocortical pyramidal cells (Szabadics et al., 2006). Thus GABAergic terminals arriving at this location may produce depolarization via GABAA receptors in this context. In hippocampal neurons the dendritic KCC2 channels can also be transiently inhibited by Ca2+ entry through voltage-gated Ca2+ channels, thus producing local changes in the dendritic Cl" gradient and affecting the efficacy of GABAA receptor inhibition, and possibly inducing plasticity at GABAergic synapses (Fiumelli et al., 2005). This is a potential mechanism to bear in mind when considering GABAergic function in the basal ganglia.
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