Segregation of Different GABA_AReceptors to Synaptic and Extrasynaptic Membranes of Cerebellar Granule Cells

Abstract

Two types of GABAA receptor-mediated inhibition (phasic and tonic) have been described in cerebellar granule cells, although these cells receive GABAergic input only from a single cell type, the Golgi cell. In adult rats, granule cells express six GABAA receptor subunits abundantly (alpha1, alpha6, beta2, beta3, gamma2, and delta), which are coassembled into at least four to six distinct GABAA receptor subtypes. We tested whether a differential distribution of GABAA receptors on the surface of granule cells could play a role in the different forms of inhibition, assuming that phasic inhibition originates from the activation of synaptic receptors, whereas tonic inhibition is provided mainly by extrasynaptic receptors. The alpha1, alpha6, beta2/3, and gamma2 subunits have been found by immunogold localizations to be concentrated in GABAergic Golgi synapses and also are present in the extrasynaptic membrane at a lower concentration. In contrast, immunoparticles for the delta subunit could not be detected in synaptic junctions, although they were abundantly present in the extrasynaptic dendritic and somatic membranes. Gold particles for the alpha6, gamma2, and beta2/3, but not the alpha1 and delta, subunits also were concentrated in some glutamatergic mossy fiber synapses, where their colocalization with AMPA-type glutamate receptors was demonstrated. The exclusive extrasynaptic presence of the delta subunit-containing receptors, together with their kinetic properties, suggests that tonic inhibition could be mediated mainly by extrasynaptic alpha6beta2/3delta receptors, whereas phasic inhibition is attributable to the activation of synaptic alpha1beta2/3gamma2, alpha6beta2/3gamma2, and alpha1alpha6beta2/3gamma2 receptors.

Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia

“…60,61 In contrast, GABA A receptors containing the d subunit, which is often coassembled with the a4 subunit in the forebrain, are selectively localized to extrasynaptic sites. [60][61][62] These extrasynaptic receptors, which have a high sensitivity to GABA and thus can be activated by ambient GABA molecules in extracellular space, mediate tonic inhibition which reduces the effects of synaptic inputs over time.…”

Molecular Targets for Antiepileptic Drug Development

“…The most notable difference in subunit composition is that the receptors mediating tonic inhibition contain the ␦ subunit, rather than the ␥ subunit characteristic of synaptic GABA A receptors. 182 Receptors containing ␣4, ␣5, or ␣6 are commonly found nonsynaptically. Pharmacologically, the most notable difference is that receptors with ␣4, ␣6, or ␦ subunits are not potentiated by benzodiazepines or by nonbenzodiazepine benzodiazepine receptor agonists (such as zolpidem), whereas those with ␣1, ␣2, ␣3, ␣5, or ␥2 subunits are benzodiazepine sensitive (TABLE 4).…”

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…In some cases, the BDZ-insensitive receptors carry a major portion of the inhibitory current (Mody, 2001;Nusser and Mody, 2002;Hamann et al, 2002). Further, it is proposed that GABA A receptors present at extrasynaptic sites on neurons (Mody, 2001;Nusser et al, 1998;Nusser and Mody, 2002) are endogenous a 4 b X d and a 6 b X d subtypes, which would be probable targets of ethanol action (Hanchar et al, 2004). Thus, in brain areas with high concentrations of BDZ-insensitive receptors containing the d subunit, ethanol could have a major effect on GABA function.…”