Context-Dependent Modulation of GABAAR-Mediated Tonic Currents

Tonic GABA currents mediated by high-affinity extrasynaptic GABA(A) receptors, are increasingly recognized as important regulators of cell and neuronal network excitability. Dysfunctional GABA(A) receptor signaling that results in modified tonic GABA currents is associated with a number of neurological disorders. Consequently, developing compounds to selectively modulate the activity of extrasynaptic GABA(A) receptors underlying tonic inhibition is likely to prove therapeutically useful. Here, we examine the GABA(A) receptor subtype selectivity of the weak partial agonist, 5-(4-piperidyl)isoxazol-3-ol (4-PIOL), as a potential mechanism for modulating extrasynaptic GABA(A) receptor-mediated tonic currents. By using recombinant GABA(A) receptors expressed in HEK293 cells, and native GABA(A) receptors of cerebellar granule cells, hippocampal neurons, and thalamic relay neurons, 4-PIOL evidently displayed differential agonist and antagonist-type profiles, depending on the extrasynaptic GABA(A) receptor isoforms targeted. For neurons, this resulted in differential modulation of GABA tonic currents, depending on the cell type studied, their respective GABA(A) receptor subunit compositions, and critically, on the ambient GABA levels. Unexpectedly, 4-PIOL revealed a significant population of relatively low-affinity gamma 2 subunitcontaining GABA, receptors in the thalamus, which can contribute to tonic inhibition under specific conditions when GABA levels are raised. Together, these data indicate that partial agonists, such as 4-PIOL, may be useful for modulating GABA(A) receptor-mediated tonic currents, but the direction and extent of this modulation is strongly dependent on relative expression levels of different extrasynaptic GABA(A) receptor subtypes, and on the ambient GABA levels.