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

  • Br J Pharmacol. 2018 Aug;175(16):3407-3421. doi: 10.1111/bph.14387.
Jeremy D Hill  1  2 ,  Viviana Zuluaga-Ramirez  1 ,  Sachin Gajghate  1 ,  Malika Winfield  1 ,  Yuri Persidsky  1  2
Affiliations
  • 1. Department of Pathology and Laboratory Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
  • 2. Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
PMID: 29888782 DOI: 10.1111/bph.14387
Abstract

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.

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