Cellular/Molecular Local Interneurons Regulate Synaptic Strength by Retrograde Release of Endocannabinoids

Neurons release endocannabinoids from their dendrites to trigger changes in the probability of transmitter release. Although such retrograde signaling has been described for principal neurons, such as hippocampal pyramidal cells and cerebellar Purkinje cells (PCs), it has not beendemonstrated for local interneurons.Herewe testedwhether inhibitory interneurons in the cerebellum, stellate cells (SCs) and basket cells, regulate the strength of parallel fiber (PF) synapses by releasing endocannabinoids. We found that depolarization-induced suppression of excitation (DSE) is present in both SCs and basket cells. The properties of retrograde inhibition were examined more thoroughly for SCs. Both DSE and synaptically evoked suppression of excitation (SSE) triggered with brief PF bursts require elevations of postsynaptic calcium, are blocked by a type 1 cannabinoid receptor (CB1R) antagonist, and are absent in mice lacking the CB1R. SSE for SCs is similar to that described previously for PCs in that it is prevented by BAPTA and DAG lipase inhibitors in the recordingpipette; however, unlike inPCs,NMDAreceptors (NMDARs)playan important role inSSE forSCs.AlthoughSCsexpressCB1Rs postsynaptically, neither high-frequency firing of SCs nor PF bursts lead to autocrine suppression of subsequent SC activity. Instead, PF bursts decrease the amplitude of disynaptic inhibition in PCs by evoking endocannabinoid release that transiently reduces the ability of PF synapses to trigger spikes in SCs. Thus, local interneuronswithin the cerebellumcan release endocannabinoids throughmetabotropic glutamate receptor- and NMDAR-dependent mechanisms and contribute to use-dependent modulation of circuit properties. Key words: 2-AG; CB1; cerebellum; DSE; NMDA receptor; stellate cel