Learning-induced modulation of the effect of endocannabinoids on inhibitory synaptic transmission

are key modulators that regulate central brain functions and behaviors, including learning and memory. At the cellular and molecular levels, endocannabinoids are potent modulators of excitatory and inhibitory synaptic function. Most effects of cannabinoids are thought to be mediated via G protein-coupled cannabinoid receptors. In particular, cannabinoids released from postsynaptic neurons are suggested to act as retrograde messengers, activating presynaptic type-1 cannabinoid receptors (CB₁Rs), thereby inducing suppression of synaptic release. Another central mechanism of cannabinoid-induced action requires activation of astroglial CB₁Rs. CB₁Rs are also implicated in self-modulation of cortical neurons. Rats that are trained in a particularly difficult olfactory-discrimination task show a dramatic increased ability to acquire memories of new odors. The memory of the acquired high-skill acquisition, termed "rule learning" or "learning set," lasts for many months. Using this behavioral paradigm, we show a novel function of action for CB₁Rs, supporting long-term memory by maintaining persistent enhancement of inhibitory synaptic transmission. Long-lasting enhancement of inhibitory synaptic transmission is blocked by a CB₁R inverse agonist. This effect is mediated by a novel purely postsynaptic mechanism, obtained by enhancing the single GABA_A channel conductance that is PKA dependent. The significant role that CB₁R has in maintaining learning-induced long-term strengthening of synaptic inhibition suggests that endocannabinoids have a key role in maintaining long-term memory by enhancing synaptic inhibition. NEW & NOTEWORTHY In this study we show a novel function and mechanism of action for cannabinoids in neurons, mediated by activation of type-1 cannabinoid receptors, supporting long-term memory by maintaining persistent enhancement of inhibitory synaptic transmission on excitatory neurons. This effect is mediated by a novel purely postsynaptic mechanism, obtained by enhancing the single GABA_A channel conductance that is PKA dependent. Thus we report for the first time that endocannabinoids have a key role maintaining learning-induced synaptic modification.