Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by α5 subunit-containing γ-aminobutyric acid type A receptors

Abstract

The principal inhibitory neurotransmitter in the mammalian brain, ␥-aminobutyric acid (GABA), is thought to regulate memory processes by activating transient inhibitory postsynaptic currents. Here we describe a nonsynaptic, tonic form of inhibition in mouse CA1 pyramidal neurons that is generated by a distinct subpopulation of GABA type A receptors (GABA ARs). This tonic inhibitory conductance is predominantly mediated by ␣5 subunit-containing GABAARs (␣5GABAARs) that have different pharmacological and kinetic properties compared to postsynaptic receptors. GABAARs that mediate the tonic conductance are well suited to detect low, persistent, ambient concentrations of GABA in the extracellular space because they are highly sensitive to GABA and desensitize slowly. Moreover, the tonic current is highly sensitive to enhancement by amnestic drugs. Given the restricted expression of ␣5GABAARs to the hippocampus and the association between reduced ␣5GABAAR function and improved memory performance in behavioral studies, our results suggest that tonic inhibition mediated by ␣5GABAARs in hippocampal pyramidal neurons plays a key role in cognitive processes. The ␥-aminobutyric acid (GABA) subtype A receptor (GABA A R) is a pentameric anion-selective ion channel that assembles from different classes of subunits (␣1-6, ␤1-3, ␥1-3, ␦, , , and ) (1). The combination of various GABA A R subunits confers different biophysical and pharmacological properties and regulates regional and subcellular patterns of distribution (2, 3). The subunit composition critically determines agonist affinity, receptor kinetics, and sensitivity to a variety of clinically important drugs, including benzodiazepines and general anesthetics.Studies of gene-targeted mice have implicated specific GABA A R subunit isoforms in critical aspects of information processing in the brain. Notably, ␣5-null mutant mice (␣5Ϫ͞Ϫ) exhibit improved performance in the water maze model of spatial learning, a hippocampus-dependent learning task (4). Further, mice carrying a point mutation at position 105 of the ␣5 subunit (H105R) experience an unexpected selective reduction of ␣5GABA A Rs in hippocampal pyramidal neurons and improved performance for learning tasks (5). Pharmacological studies further support the involvement of ␣5GABA A Rs in learning processes; for example, ␣5 subunit-selective inverse agonists such as L-655,708 enhance learning performance in rats in the Morris water maze test (6, 7). Moreover, ␣5 subunitselective inverse agonists exhibit desirable nootropic effects without causing adverse convulsant activities associated with nonselective GABA A R inverse agonists. Thus, inhibition of ␣5GABA A Rs presents an attractive strategy for developing memory-enhancing drugs.The neuronal substrates underlying improved cognitive performance associated with reduced ␣5GABA A R function remain unknown. The ␣5 subunit has a unique and limited pattern of distribution in the mammalian brain. Although ␣5-containing receptors constitute Ͻ5% of the total GABA A R population...

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

“…Most extrasynaptic populations contain the δ subunit, which confers high sensitivity to GABA and minimal desensitization (Saxena andMacdonald, 1997, Bianchi et al, 2002a;Brown et al, 2002), properties ideally suited for maintenance of a tonic current in response to ambient levels of GABA. The α5βxγ2 receptors are also primarily located extrasynaptically in the CA regions of the hippocampus (Caraiscos et al, 2004). Our findings that these receptors show minimal levels of desensitization are consistent with their contribution to a long-lasting tonic current.…”

Activin tunes GABAergic neurotransmission and modulates anxiety-like behavior

“…Recent evidence from CA1 pyramidal cells suggests indeed that, besides a5GABA A Rs, 30,38 a4GABA A Rs (combined with d-subunit) participate in tonic inhibition. 22 Since a4GABA A Rs are benzodiazepine-insensitive, their apparent upregulation in tg CA1 pyramidal cells (at the expense of benzodiazepine-sensitive GABA A Rs) could be in part responsible for the reduced diazepam sensitivity in tg CA1 pyramidal cells.…”

Propofol enhances both tonic and phasic inhibitory currents in second-order neurons of the solitary tract nucleus (NTS)

“…Tonic GABA A currents increase during development in cerebellar neurons (Brickley et al, 1996) and anesthetic sensitivity of tonic currents can be much greater than for phasic events, for example Belelli et al (2005). The relative insensitivity of tonic currents in NTS neurons for propofol contrasts with the high sensitivity for tonic GABA A currents in hippocampal and neocortical neurons to propofol and isoflurane (Bai et al, 2001;Caraiscos et al, 2004a;Caraiscos et al, 2004b;Drasbek et al, 2007). This contrasting pattern of NTS compared to forebrain regions may represent differences in GABA A receptor subunit composition (Feng & Macdonald, 2004;Caraiscos et al, 2004a) and/or extrasynaptic cellular loci (Yeung et al, 2003).…”

“…The relative insensitivity of tonic currents in NTS neurons for propofol contrasts with the high sensitivity for tonic GABA A currents in hippocampal and neocortical neurons to propofol and isoflurane (Bai et al, 2001;Caraiscos et al, 2004a;Caraiscos et al, 2004b;Drasbek et al, 2007). This contrasting pattern of NTS compared to forebrain regions may represent differences in GABA A receptor subunit composition (Feng & Macdonald, 2004;Caraiscos et al, 2004a) and/or extrasynaptic cellular loci (Yeung et al, 2003). Indeed, a unique possibility might include actions of propofol on GABA A receptors containing ρ 1 subunits which are expressed in NTS (Milligan et al, 2004).…”