The endogenous cannabinoid system gates plasticity of tonic GABA inhibition

receptors by 'ambient' GABA. Changes in the efficacy of GABAergic transmission are important mechanisms contributing to experience-dependent modifications of brain function. Mechanisms underlying changes in synaptic GABAergic efficacy have been investigated and, among them, endocannabinoid (eCB)‑dependent GABAergic synaptic plasticity is a well‑characterised mechanism. Little, however, is known about the potential control of, for example, eCB signalling on extrasynaptic GABA tone. By using whole-cell patch-clamp recordings, we showed that a brief depolarisation of cortical pyramidal neurons is associated with a transient increase in tonic GABA inhibition that is dependent on CB1 receptor activity and eCB mobilisation. In addition, we showed that this depolarisation-dependent plasticity of tonic inhibition does not arise from the transient increase of ambient GABA concentration but requires intracellular neurosteroid synthesis since the pharmacological inhibition of the P450scc enzyme responsible for the neurosteroid cascade synthesis blunted this phenomenon. These data provide evidence that, under sustained neuronal activity, eCBs and neurosteroids are engaged to finely tune tonic extrasynaptic GABAergic inhibition in activated neurons. KEY POINTS: Besides phasic synaptic inhibition, GABA mediates a form of tonic extrasynaptic inhibition. The physiological mechanisms that tune the tonic GABA inhibition are largely unclear. Here we show that brief depolarisation of cortical pyramidal neurons transiently and reversibly potentiates tonic GABA inhibition. Increased extracellular GABA concentration or changes in GABA turnover do not account for plasticity of tonic inhibition. Endocannabinoid signalling and neurosteroids are required for plasticity of tonic GABA inhibition.