Regular firing of a single output neuron reduces its own inhibition through endocannabinoids in substantia nigra pars reticulata of juvenile mice

Depolarization-induced suppression of inhibition in substantia nigra pars reticulata suggests that burst-like activity but not regular firing suffices to activate presynaptic endocannabinoid CB1 receptors. To more closely determine the type of activity required, we applied gramicidin perforated patch recording under visual control to substantia nigra slices of juvenile mice. We found that evoked inhibitory postsynaptic currents (eIPSCs) were reduced in amplitude by the spontaneous firing of a neuron under study, whereas silencing this neuron enhanced inhibitory responses. Autonomous firing reduced eIPSCs to 78%±2% in a time- but not frequency-dependent manner. The phenomenon which we termed firing-induced suppression of inhibition was cannabinoid receptor subtype 1–dependent, whereas adenosine A1 receptors played only a minor role. Depletion of intracellular Ca²⁺ stores abolished the firing-induced suppression of inhibition suggesting that Ca²⁺ release from internal stores is necessary for the production of endocannabinoids during autonomous firing. We suggest that the Ca²⁺ influx during autonomous activity of pars reticulata neurons suffices to selectively dampen incoming inhibition from striatal neurons because it is amplified by ryanodine receptor-mediated Ca²⁺ release from intracellular stores.