Finally, the relation between DSI/DSE and other forms of long‐ and short‐term synaptic inhibition, which were more recently associated with the production of endocannabinoids by postsynaptic cells.

The possible modes of induction of DSI/DSE by physiological activity patterns, and the partially conflicting evaluations of the calcium concentration increases required for cannabinoid synthesis.

The more recent research that has led to the identification of endocannabinoids as the retrograde messengers responsible for DSI/DSE.

The evidence accumulated during the 1990s that has led to the conclusion that DSI/DSE rely on retrograde signaling.

Depolarization‐induced suppression of inhibition (DSI) and depolarization‐induced suppression of excitation (DSE) are two related forms of short‐term synaptic plasticity of GABAergic and glutamatergic transmission, respectively. They are induced by calcium concentration increases in postsynaptic cells and are mediated by the release of a retrograde messenger, which reversibly inhibits afferent synapses via presynaptic mechanisms.

Abbreviations:

2‐AG 2‐Arachidonyl glycerol CB1Rs type 1 cannabinoid receptors CCK cholecystokinin DAG diacylglycerol DSE depolarization‐induced suppression of excitation DSI depolarization‐induced suppression of inhibition LTD long‐term depression mGluR metabotropic glutamate receptors PLC phospholipase C eIPSCs evoked inhibitory postsynaptic currents sIPSCs spontaneous inhibitory postsynaptic currents mIPSCs miniature inhibitory postsynaptic currents

Conclusion It is clear that research on endocannabinoids has a bright future waiting ahead. We are still at a very early stage, but there is every reason to believe that endocannabinoids play a fundamental role in the functioning of the mammalian brain. DSI/DSE is presumably only a small component of it. This component is nevertheless of primary importance, because it has suddenly put retrograde signaling in the limelight, and it has revealed a kind of neuronal signaling that is fundamentally different from that exerted by classical neurotransmitters. One of the greatest challenges at this stage is to Figure 1a establish the physiological role of DSI/DSE, but it can be hoped that, with research now starting to concentrate on this issue, a clear answer will be available soon.