Reduction in endocannabinoid tone is a homeostatic mechanism for specific inhibitory synapses

When chronic alterations in neuronal activity occur, network gain is maintained by global homeostatic scaling of synaptic strength, but the stability of microcircuits can be controlled by unique adaptations that differ from the global changes. It is not understood how specificity of synaptic tuning is achieved. Here we report that, while a large population of inhibitory synapses is homeostatically scaled down after chronic inactivity, decreased endocannabinoid tone specifically strengthens a subset of GABAergic synapses that express cannabinoid receptors. In hippocampal slice cultures of rats, a 3–5 day blockade of neuronal firing facilitates uptake and degradation of anandamide. The consequent reduction in basal stimulation of cannabinoid receptors augments GABA release probability, thus fostering rapid depression of synaptic inhibition and on-demand disinhibition. This novel regulatory mechanism, mediated by activity-dependent changes in tonic endocannabinoid level, permits selective local tuning of inhibitory synapses in hippocampal networks.