Presynaptic cannabinoid sensitivity is a major determinant of depolarization-induced retrograde suppression at hippocampal synapses.

Recent studies have clarified that endogenous cannabinoids (endocannabinoids) are released from depolarized postsynaptic neurons in a Ca(2+)-dependent manner and act retrogradely on presynaptic cannabinoid receptors to suppress inhibitory or excitatory neurotransmitter release. This type of modulation has been found in the hippocampus and cerebellum and was called depolarization-induced suppression of inhibition (DSI) or excitation (DSE). In this study, we quantitatively examined the effects of postsynaptic depolarization and a cannabinoid agonist on excitatory and inhibitory synapses in rat hippocampal slices and cultures. We found that both DSE and DSI can be induced, but DSE was much less prominent than DSI. For the induction of DSE, the necessary duration of depolarization was longer than for DSI. The magnitude of DSE was much smaller than that of DSI. To explore the reasons for these differences, we tested the sensitivity of EPSCs and IPSCs to a cannabinoid agonist, WIN55,212-2, in hippocampal cultures. IPSCs were dichotomized into two distinct populations, one with a high sensitivity to WIN55,212-2 (50% block at 2 nm) and the other with no sensitivity. In contrast, EPSCs were homogeneous and exhibited a low sensitivity to WIN55,212-2 (50% block at 60 nm). We estimated that the 5 sec depolarization elevated the local endocannabinoid concentration to a level equivalent to several nanomoles of WIN55,212-2. Using CB1 knock-out mice, we verified that both DSI and DSE were mediated by the cannabinoid CB1 receptor. These results indicate that presynaptic cannabinoid sensitivity is a major factor that determines the extent of DSI and DSE.