Ionotropic receptors of γ-aminobutyric acid (GABA receptors of type A, GABA_ARs) are the main receptor type that generates inhibitory interneuronal signaling in the brain. The classical form of GABA_AR-induced inhibitory signal is phasic inhibition: a short synchronized opening of GABA_ARs in a synapse, generated by the binding of GABA released from a presynaptic terminal. However, there is an alternative form of inhibition: charge transfer through continuously active GABA_ARs, or tonic inhibition, detected in peripheral nervous system in the 1970s (Brown, 1979) but documented for the central nervous system only in the 1990s (Otis et al., 1991; Brickley et al., 1996). The classical view is that tonic inhibition is generated in response to GABA, which is continuously present in the extracellular space of neural tissue due to spillover from synapses or release from astroglia and/or neurogliaform cells (Farrant and Nusser, 2005; Kozlov et al., 2006; Oláh et al., 2009). This implies the generation of a continuous inhibitory tone mainly by perisynaptic and extrasynaptic GABA_ARs, since the vast majority of transporters which perform reverse uptake of GABA are localized in synapses or in their immediate vicinity (Minelli et al., 1996; Chiu et al., 2002; Conti et al., 2004). Hence, the magnitude of tonic GABA_ARs-delivered current is considered to be regulated by the availability of extracellular GABA, and by the quantity of GABA_ARs at an extrasynaptic surface of a given neuron (Glykys and Mody, 2007). Later research, however, revealed that a significant part of tonic inhibition mediated by GABA_ARs is independent of GABA binding, i.e., it is delivered by spontaneously opening GABA_ARs (s-GABA_ARs). s-GABA_ARs in that study were shown to be insensitive to the competitive GABA antagonist SR-95531 (SR), but could be suppressed by the GABA_AR open channel blocker picrotoxin (PTX), and, to the less extent, by competitive GABA antagonist bicuculline (BIC; McCartney et al., 2007).

In the last few decades, studies of GABA_ARs-mediated tonic currents have attracted a considerable interest, and have described a functional role of this form of inhibition in a number of brain areas; in particular, its important input into neural excitability, synaptic plasticity, neurogenesis and network oscillations (Mody and Pearce, 2004; Farrant and Nusser, 2005; Glykys and Mody, 2007). Since our understanding of underlying mechanisms is still far from excellent, the newly discovered type of tonic conductance delivered via s-GABA_ARs promises a conceptual breakthrough in the field. Nevertheless, despite the phenomenon of GABA-independent gating of GABA_ARs being reported in numerous publications (Neelands et al., 1999; Birnir et al., 2000; Maksay et al., 2003; Miko et al., 2004), until recently the functional role of s-GABA_ARs in living neural tissue has remained beyond the focus of neuroscience research.

In this article, we try to summarize the data available to date on s-GABA_ARs function in neural transmission and to discuss perspective directions for further studies which should clarify the role of s-GABA_ARs under normal conditions and in pathology.

To date, there have been only a few publications highlighting the functional properties of s-GABA_ARs in living neurons. This imposes obvious limitations on conclusions in terms of the applicability for different brain regions and types of neurons. Nevertheless, the significant input of s-GABA_ARs into the modulation of output signal generation and into the integration of input signaling in a given neuron, suggests that s-GABA_AR activity is one of the key actors that regulate neural inhibition.

Indeed, the relative importance of GABA-independent s-GABA_ARs signaling in a given region of the brain depends critically on the native concentration of GABA in the extracellular space. Different groups report in vivo concentrations varying by more than an order of magnitude: from less than 100 (Wlodarczyk et al., 2013) or 200 (Glaeser and Hare, 1975) nM to units of micromoles (Tossman et al., 1986; Takagi et al., 1993). Moreover, there may be local inhomogeneities of GABA concentrations due to cell-specific differences in the distribution and/or activity of GABA transporters and the elements of the GABA synthesis system. This was indirectly confirmed by the observation that the silencing of GAD-65 activity reduces tonic inhibitory currents in interneurons, but not in the pyramidal neurons of the hippocampal CA1 area (Song et al., 2011). A recent study on the hippocampus has demonstrated that at a GABA concentration of ~100 nM, the amount of GABA-induced tonic current (which can be suppressed by SR) is close to statistical noise (see example at Figure 1), and negligible when compared to that through GABA-independent openings of s-GABA_ARs (Wlodarczyk et al., 2013); on the contrary, SR has been shown to reveal a huge amount of tonic GABA-dependent current in thalamus (Cope et al., 2005). These data suggest that the relative impact of s-GABA_ARs into neural signaling varies widely, depending on the particular brain region and cell type. To the best of our knowledge, previous articles that discuss lower EC₅₀ values (i.e., higher potency) of extrasynaptic GABA_ARs in vivo do not consider spontaneous channels and how they influence such measurements. This fact enforces the importance of the work on s-GABA_ARs pharmacology for an understanding of biophysical phenomena in living neurons.

The important question regarding s-GABA_ARs is whether or not these receptors represent a convergent group with similar functional properties, or if they share common receptor subunit(s). Numerous studies have attributed the majority (up to 75%) of GABA_AR-delivered tonic inhibition to δ-containing GABA_ARs (Stell et al., 2003), which are abundant at extrasynaptic membranes (Nusser et al., 1998) but have been also found in synapses where they make a significant input into phasic inhibition (Sun et al., 2018), and in perisynaptic loci (Wei et al., 2003). The remaining portion of tonic inhibition is, to a large extent but not fully, produced by receptors containing the α5-subunit (Farrant and Nusser, 2005). Furthermore, the agonist-independent GABA_AR openings were observed under similar conditions for receptors of three different subunit compositions (Mortensen et al., 2010). In addition, the observation that mutations in α1 and β2 subunits modulate spontaneous GABA_ARs gating (Baptista-Hon et al., 2017) prevents us from ruling out these subunits as potential alternative candidates to be involved in the formation of s-GABA_ARs. Combined with the facts of the GABA-independent tonic activity of α4-GABA_ARs (Tang et al., 2010) and spontaneous openings of α2β1ε-GABA_ARs which contribute to the baseline currents in whole-cell recordings (Wagner et al., 2005), the abovementioned data on GABA-independent activity suggest that GABA-independent inhibition is of poly-subtype origin, with a substantial part inherent in the non-δ- and non-α5-containing receptors.

In view of numerous subunits and subunit compositions of GABA_AR which demonstrate spontaneous gating, the obvious question is: are there GABA_ARs subtype(s) which do not demonstrate GABA-independent activity? The existence of such GABA_ARs was suggested by the study showing that, in contrast to the α2α1ε receptor, responses of α2β1 and α2β1γ2-GABA_ARs do not produce a “baseline overshoot” associated with spontaneous openings (Wagner et al., 2005).

Therefore, data collected to date suggest revision of two traditional views, now common in fundamental neuroscience: (i) that tonic inhibitory conductance is generated by ambient GABA (due to proven significance of s-GABA_ARs input); and (ii) that tonic and phasic inhibition are mediated by different GABA_ARs subtypes (due to growing evidence that typical extrasynaptic GABA_ARs can make a significant contribution into IPSCs via a synaptic and/or perisynaptic presence).

It has been demonstrated that a scarcity of α1 subunit is correlated with resistance to anti-epileptic drugs (Bethmann et al., 2008), whereas increased α1-GABA_AR expression in the hippocampus suppresses the development of temporal lobe epilepsy (TLE; Raol et al., 2006). Apart from that, it was shown that phasic GABA-ergic inhibition is lowered in TLE, whereas tonic GABA-ergic conductance remains intact (Palma et al., 2007; Pavlov et al., 2011), making tonic GABA-ergic current a perspective target for TLE treatment. The classical paradigm, where extracellular GABA triggers tonic GABA-ergic current, implies that the most effective therapeutic approach is to increase the concentration of GABA in the cerebrospinal fluid, and thus augment inhibitory conductance. However, this approach was repeatedly found to be ineffective (Cohen et al., 2002; Glykys et al., 2009) or even one that leads to epileptogenesis (Palma et al., 2006; Cope et al., 2009) due to various side effects. These side effects impose limitations on the clinical use of specific antiepileptic drugs that increase the concentration of GABA in cerebrospinal fluid (Sander and Hart, 1990; Leppik, 1995). In contrast, the modulation of s-GABA_ARs in GABA-independent manner promises an alternative for TLE treatment through the regulation of tonic conductance without the need to interfere with extracellular GABA concentration, thus avoiding the afore mentioned side effects.

Apart from the potential of α1-GABA_ARs for TLE treatment, α5-GABA_ARs (which also display GABA-independent activity) were found to be a perspective target for schizophrenia treatment (Lodge and Grace, 2011). Taking into account similar concentration of GABA found in vivo in the brains of schizophrenic patients and of a control group (Tayoshi et al., 2010), and the well-established fact that changes in tonic GABA-ergic inhibition are involved in the generation of schizophrenia symptoms (Damgaard et al., 2011), these data suggest a potentially important role of drugs targeting s-GABA_ARs in the suppression of schizophrenia development, since action through s-GABA_ARs in GABA-independent manner eliminates the need to modify GABA concentration in cerebrospinal fluid.

Another clinical implication of s-GABA_ARs rises from the fact that sedative and analgesic effects of gaboxadol (THIP) are mediated exclusively by α4-containing GABA_ARs (Chandra et al., 2006), that demonstrate GABA-independent activity.

NO and SS contributed to the conception and design of the article. NO received data displayed at the figure and analyzed literature connected to the topic, contributed to manuscript revision. SS wrote the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.