Activation of GPR55 increases neural stem cell proliferation and promotes early adult hippocampal neurogenesis.

BACKGROUND AND PURPOSE:The cannabinoid system exerts functional regulation of neural stem cell (NSC) proliferation and adult neurogenesis, yet not all effects of cannabinoid-like compounds seen can be attributed to the cannabinoid 1 (CB₁ ) or CB₂ receptor. The recently de-orphaned GPR55 has been shown to be activated by numerous cannabinoid ligands suggesting that GPR55 is a third cannabinoid receptor. Here, we examined the role of GPR55 activation in NSC proliferation and early adult neurogenesis. EXPERIMENTAL APPROACH:The effects of GPR55 agonists (LPI, O-1602, ML184) on human (h) NSC proliferation in vitro were assessed by flow cytometry. Human NSC differentiation was determined by flow cytometry, qPCR and immunohistochemistry. Immature neuron formation in the hippocampus of C57BL/6 and GPR55^-/- mice was evaluated by immunohistochemistry. KEY RESULTS:Activation of GPR55 significantly increased proliferation rates of hNSCs in vitro. These effects were attenuated by ML193, a selective GPR55 antagonist. ML184 significantly promoted neuronal differentiation in vitro while ML193 reduced differentiation rates as compared to vehicle treatment. Continuous administration of O-1602 into the hippocampus via a cannula connected to an osmotic pump resulted in increased Ki67+ cells within the dentate gyrus. O-1602 increased immature neuron generation, as assessed by DCX+ and BrdU+ cells, as compared to vehicle-treated animals. GPR55^-/- animals displayed reduced rates of proliferation and neurogenesis within the hippocampus while O-1602 had no effect as compared to vehicle controls. CONCLUSIONS AND IMPLICATIONS:Together, these findings suggest GPR55 activation as a novel target and strategy to regulate NSC proliferation and adult neurogenesis. © 2018 The British Pharmacological Society.

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