Endogenous cannabinoids are lipid-based ligands of the main cannabinoid receptors type 1 and 2 (CB1R and CB2R). In contrast to the well-studied effects of CB1Rs, much less is known about the physiological role of CB2Rs in the central nervous system (CNS). In fact, CB2Rs were considered as peripheral cannabinoid receptors representing the complementary cannabinoid receptor to the CB1R in the CNS. However recent pharmacological, behavioral and genetic studies have determined the presence of functional CB2Rs in the brain and their involvement in various physiological and pathological conditions. Endocannabinoids are produced in an activity-dependent manner. Next to their well-described role as retrograde modulators of synaptic transmission, endocannabinoids also mediate a cell-autonomous slow self-inhibition (SSI). Action potential-driven endocannabinoid production followed by binding to cannabinoid receptors induces a long-lasting hyperpolarization of the membrane potential, rendering the cell less excitable. Several studies described different endocannabinoid receptors and cellular mechanisms by which SSI is implemented in different cell types and brain areas: While pyramidal cells and interneurons in the somatosensory cortex were reported to mediate SSI via CB1Rs and G protein-coupled inward rectifying K+ (GIRK) channels, hippocampal principal cells were shown to mediate SSI in a CB2R mediated and input-resistance-independent manner. However, the molecular mechanism by which the long-lasting hyperpolarization is implemented was not clear. During my thesis I was part of a team that demonstrated that hippocampal SSI is mediated via activation of the Na+/bicarbonate cotransporter. In order to get further insight in the occurrence of SSI in different classes of neurons, we analyzed the presence of SSI in one type of hippocampal interneuron and showed that oriens-lacunosum moleculare (OLM) interneurons do not express SSI. Further, we investigate SSI in different neuron types of layer 2/3 in the primary somatosensory cortex and show that regular firing cells express SSI in contrast to fast-spiking interneurons. Trains of action potentials induced a long-lasting hyperpolarization that was accompanied by a change in input resistance due to GIRK channel activation. By using cannabinoid receptor-specific pharmacology as well as transgenic mice lacking either CB1Rs or CB2Rs, we demonstrate that this effect is mediated by CB2R activation. Taken together, hippocampal and cortical SSI both represent a CB2R-dependent mechanism; however the underlying mechanism by which the hyperpolarization is implemented differs between the different brain regions. By describing an additional cellular mechanism for SSI induction, these findings add further insights on the physiological role of CB2Rs and expand our knowledge about cell type-specific differential cannabinoid signaling. Moreover, these findings suggest CB2Rs as a promising target for therapeutic approaches.
