Endocannabinoids are widely regarded as negative modulators of presynaptic release. Here, we present evidence that in visual cortex endocannabinoids are crucial for the maturation of GABAergic release. We found that between eye opening and puberty, release changes from an immature state with high release probability, short-term depression (STD), and high release variability during irregular patterned activity, to a mature state with reduced release probability, STD, and variability. This transition requires visual experience and stimulation of CB1 cannabinoid receptors as it is mimicked by administration of CB1 agonists, blocked by antagonists, and is absent in CB1R KO mice. In immature slices, activation of CB1 receptors induces long-term depression of inhibitory responses (iLTD) and a reduction in STD and response variability. Based on these findings, we propose that visually induced endocannabinoid-dependent iLTD mediates the developmental decrease in release probability, STD, and response variability, which are characteristic of maturation of cortical GABAergic inhibition.
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