["The Journal of Physiology, Volume 604, Issue 12, Page 4984-5010, 15 June 2026. ", "\nAbstract figure legend Postsynaptic depolarisation and increases in intracellular Ca2+ ([Ca2+]i) trigger the synthesis of endocannabinoids (eCBs), which are hypothesised to enhance tonic GABAergic inhibition via two primary pathways. In the proposed autocrine mechanism, eCBs activate postsynaptic somatodendritic or mitochondrial CB1 receptors, stimulating de novo neurosteroidogenesis via the P450scc enzyme; notably, eCBs may also modulate GABAA receptors through direct binding. Alternatively, in the proposed paracrine pathway, eCBs act as retrograde messengers at presynaptic and astrocytic CB1 receptors, triggering the extracellular release of neurosteroids that subsequently act on postsynaptic extrasynaptic GABAA receptors.\n\n\n\n\n\n\n\n\n\nAbstract\nGABAergic neurotransmission generates two types of inhibition: a phasic inhibition, determined by the transient activation of synaptic GABAA receptors, that elicits inhibitory postsynaptic currents, and a tonic inhibition caused by persistent activation of extrasynaptic GABAA 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.\n\n\n\n\n\n\n\n\n\nKey points\n\nBesides phasic synaptic inhibition, GABA mediates a form of tonic extrasynaptic inhibition.\nThe physiological mechanisms that tune the tonic GABA inhibition are largely unclear.\nHere we show that brief depolarisation of cortical pyramidal neurons transiently and reversibly potentiates tonic GABA inhibition.\nIncreased extracellular GABA concentration or changes in GABA turnover do not account for plasticity of tonic inhibition.\nEndocannabinoid signalling and neurosteroids are required for plasticity of tonic GABA inhibition.\n\n\n"]