GABA_AReceptor-Mediated Tonic Inhibition in Thalamic Neurons

Abstract

Tonic GABA A receptor-mediated inhibition is typically generated by ␦ subunit-containing extrasynaptic receptors. Because the ␦ subunit is highly expressed in the thalamus, we tested whether thalamocortical (TC) neurons of the dorsal lateral geniculate nucleus (dLGN) and ventrobasal complex exhibit tonic inhibition. Focal application of gabazine (GBZ) (50 M) revealed the presence of a 20 pA tonic current in 75 and 63% of TC neurons from both nuclei, respectively. No tonic current was observed in GABAergic neurons of the nucleus reticularis thalami (NRT). Bath application of 1 M GABA increased tonic current amplitude to ϳ70 pA in 100% of TC neurons, but it was still not observed in NRT neurons. In dLGN TC neurons, the tonic current was sensitive to low concentrations of the ␦ subunit-specific receptor agonists allotetrahydrodeoxycorticosterone (100 nM) and 4,5,6,7-tetrahydroisoxazolo[5,4-c]-pyridin-3-ol (THIP) (100 nM) but insensitive to the benzodiazepine flurazepam (5 M). Bath application of low concentrations of GBZ (25-200 nM) preferentially blocked the tonic current, whereas phasic synaptic inhibition was primarily maintained. Under intracellular current-clamp conditions, the preferential block of the tonic current with GBZ led to a small depolarization and increase in input resistance. Using extracellular single-unit recordings, block of the tonic current caused the cessation of low-threshold burst firing and promoted tonic firing. Enhancement of the tonic current by THIP hyperpolarized TC neurons and promoted burst firing. Thus, tonic current in TC neurons generates an inhibitory tone. Its modulation contributes to the shift between different firing modes, promotes the transition between different behavioral states, and predisposes to absence seizures.

Excitability of cortical neurons depends upon a powerful tonic conductance in inhibitory networks

“…In this way, tonic inhibition on LTS cells would be an extrinsic, rather than intrinsic, regulator. This role of tonic inhibition in the cortex favoring slow wave activity associated with sleep fits with tonic inhibition in the thalamus promoting bursting and slow-wave activity (Belelli et al, 2005;Cope et al, 2005). With regard to this hypothesis, it is of interest whether FS cells have the same degree of tonic GABA A -mediated inhibition as LTS cells.…”

GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

“…During the last decade, several studies have shown that GABA A receptor activation can also mediate tonic inhibition; these receptors are extrasynaptically and perisynaptically localized and contain a distinct, high affinity subunit composition made of δ and α4, α5 & α6 subunits (Nusser et al, 1998;Yeung et al, 2003;Semyanov et al, 2003Semyanov et al, , 2004Cope et al, 2005;Scimemi et al, 2005;Glykys et al, 2008). Hence, GABA A receptors can generate two types of current, depending on their location and subunit composition: the first type is the classic synaptic phasic (or 'transient') current that results from the release of GABA from synaptic vesicles in the synaptic cleft; the second type is a tonic ('always on') current that is caused by GABA A receptors responding to low levels of ambient GABA (Farrant and Nusser, 2005).…”

Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions

“…So far, it is not known whether this complex regulation of tonic inhibition is related to the heterogeneity of extrasynaptic GABA A receptors in granule cells. However, it should be emphasized that the role of the d subunit is forming receptors mediating tonic inhibition is not restricted to the cerebellum, but also occurs in thalamus and hippocampus (35,36). Furthermore, these receptors Note that Lugaro cells innervate all cell types in the molecular layer except PC.…”