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Activation of GPR55 increases neural stem cell proliferation and promotes early adult hippocampal neurogenesis
Author(s) -
Hill Jeremy D,
ZuluagaRamirez Viviana,
Gajghate Sachin,
Winfield Malika,
Persidsky Yuri
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14387
Subject(s) - neurogenesis , dentate gyrus , cannabinoid receptor , neural stem cell , cannabinoid , hippocampal formation , endocannabinoid system , biology , microbiology and biotechnology , hippocampus , pharmacology , stem cell , receptor , endocrinology , antagonist , biochemistry
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 (CB 1 ) or CB 2 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.