A putative lysophosphatidylinositol receptor GPR55 modulates hippocampal synaptic plasticity

Abstract

GPR55, an orphan G-protein coupled receptor, is activated by lysophosphatidylinositol (LPI) and the endocannabinoid anandamide, as well as by other compounds including THC. Such signaling molecules are capable of modulating synaptic plasticity. LPI is a potent endogenous ligand of GPR55 and neither GPR55 nor LPIs’ functions in the brain are well understood. While endocannabinoids are well known to modulate brain synaptic plasticity, the potential role LPI could have on brain plasticity has never been demonstrated. Therefore, we examined not only GPR55 expression, but also the role its endogenous ligand could play in long-term potentiation, a common form of synaptic plasticity. Using quantitative RT-PCR, electrophysiology, and behavioral assays, we examined hippocampal GPR55 expression and function. qRT-PCR results indicate that GPR55 is expressed in hippocampi of both rats and mice. Immunohistochemistry and single cell PCR demonstrates GPR55 protein in pyramidal cells of CA1 and CA3 layers in the hippocampus. Application of the GPR55 endogenous agonist LPI to hippocampal slices of GPR55+/+ mice significantly enhanced CA1 LTP. This effect was absent in GPR55−/− mice, and blocked by the GPR55 antagonist CID 16020046. We also examined paired-pulse ratios of GPR55−/− and GPR55+/+ mice with or without LPI and noted significant enhancement in paired-pulse ratios by LPI in GPR55+/+ mice. Behaviorally, GPR55−/− and GPR55+/+ mice did not differ in memory tasks including novel object recognition, radial arm maze, or Morris water maze. However, performance on radial arm maze and elevated plus maze task suggests GPR55−/− mice have a higher frequency of immobile behavior. This is the first demonstration of LPI involvement in hippocampal synaptic plasticity.

Structure-Activity Relationship of the GPR55 Antagonist, CID16020046

“…ML193 also blocks pro-nociceptive effects of LPI and LPI-evoked depolarisation of neurons from a brain region, the periaqueductal grey [15], reinforcing previous data linking GPR55 to pain perception [16,17]. CID16020046 has been used to understand the role of GPR55 in the cardiovascular system [12,18,19], in atherosclerosis and intestinal inflammation [20][21][22], and in brain [23]. CID16020046 has extended the association of GPR55 to cancer, blocking LPI-evoked angiogenesis in ovarian carcinoma and migration of breast cancer cells [24,25].…”

Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome

“…Given that CBD's most robust effects are on inhibitory neurons, we next sought to identify the molecular target through which CBD enhances inhibitory signaling. Numerous CBD targets in the brain have been identified (35), including the lipid-activated G proteincoupled receptor GPR55 (36,37), which is expressed in both interneurons and excitatory neurons in the dentate gyrus and other regions of the hippocampus and modulates hippocampal synaptic plasticity [Allen Brain Atlas (38)]. To determine if CBD antagonism of GPR55 contributed to our observed CBD-induced enhancement of inhibitory signaling, we bath-applied the GPR55 antagonist CID16020046 (CID, 10 μM) (39) and measured the effect of CBD on DGC output and inhibitory neuron signaling.…”

G-Protein-Coupled Receptors in CNS: A Potential Therapeutic Target for Intervention in Neurodegenerative Disorders and Associated Cognitive Deficits

“…GPR55 is highly expressed in the pyramidal cells in the hippocampal CA1 and CA3 layers and modulates the synaptic plasticity of pyramidal cells [173]. However, GPR85 is highly expressed in the dentate gyrus region of the hippocampus [174,175] and prominently expresses in the phases of neuronal differentiation in the developing cerebral cortex [176].…”