A novel crosstalk within the endocannabinoid system controls GABA transmission in the striatum

A Musella,D Centonze,L Guadalupi,A Gentile,F R Rizzo,F De Vito,G Mandolesi,S Bullitta,D Fresegna

doi:10.1038/s41598-017-07519-8

Abstract

The N-palmitoylethanolamine (PEA) is an endogenous member of the endocannabinoid system (ECS) with several biological functions, including a neuromodulatory activity in the central nervous system. To shed light on the neuronal function of PEA, we investigated its involvement in the control of both excitatory and inhibitory transmission in the murine striatum, a brain region strongly modulated by the ECS. By means of electrophysiological recordings, we showed that PEA modulates inhibitory synaptic transmission, through activation of GPR55 receptors, promoting a transient increase of GABAergic spontaneous inhibitory postsynaptic current (sIPSC) frequency. The subsequently rundown effect on sIPSC frequency was secondary to the delayed stimulation of presynaptic cannabinoid CB1 receptors (CB1Rs) by the endocannabinoid 2-AG, whose synthesis was stimulated by PEA on postsynaptic neurons. Our results indicate that PEA, acting on GPR55, enhances GABA transmission in the striatum, and triggers a parallel synthesis of 2-AG at the postsynaptic site, that in turn acts in a retrograde manner to inhibit GABA release through the stimulation of presynaptic CB1Rs. This electrophysiological study identifies a previously unrecognized function of PEA and of GPR55, demonstrating that GABAergic transmission is under the control of this compound and revealing that PEA modulates the release of the endocannabinoid 2-AG.

Highlights

In the last two decades, many physiological studies have substantially contributed to discover additional endogenous member of the endocannabinoid system (ECS) provided with distinct biological actions[1]
PEA is an endogenous congener of the endocannabinoid anandamide (AEA) and is usually biosynthesized through similar metabolic pathways and enzymes together with AEA8 but, unlike AEA, PEA predominantly acts on G-protein coupled receptor, GPR559, 10, showing low affinity for both type-1 and type-2 cannabinoid receptors (CB1 and CB2) and for TRPV1 channels[3, 11]
Since it was reported that PEA acts as a GPR55 receptor agonist[9, 10] and the GPR55 receptor was localized in the striatum of both humans and mice[14, 15], we further characterized PEA-mediated synaptic alteration by performing electrophysiological recordings in the presence of a GPR55 antagonist, CID-1602

Summary

Introduction

In the last two decades, many physiological studies have substantially contributed to discover additional endogenous member of the endocannabinoid system (ECS) provided with distinct biological actions[1]. GPR55 receptors have been heavily implicated in immunomodulatory functions but less is known about their effects on neuronal cells. These receptors are widely expressed in the brain and have been found significantly expressed in the striatum, their cellular and subcellular localization is still unclear[12,13,14,15]. Our results show that PEA, by acting on the same receptors, stimulates synthesis and delayed synaptic effects of the other endocannabinoid 2-AG, giving rise to a previously unrecognized feed-back control of GABA transmission mediated by endocannabinoids

Methods

Results

Conclusion