Centro Europeo per la Ricerca sul Cervello (CERC), IRCCS Fondazione Santa Lucia, 00143, Rome, Italy.
Unit of Neurology and of Neurorehabilitation, IRCCS Istituto Neurologico Mediterraneo (INM) Neuromed, 86077, Pozzilli (IS), Italy.
Sci Rep. 2017 Aug 4;7(1):7363. doi: 10.1038/s41598-017-07519-8.
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.
N-棕榈酰乙醇胺（PEA）是内源性大麻素系统（ECS）的成员，具有多种生物学功能，包括在中枢神经系统中的神经调节活性。为了阐明 PEA 的神经元功能，我们研究了其在控制小鼠纹状体中兴奋性和抑制性传递中的作用，纹状体是受 ECS 强烈调节的大脑区域。通过电生理记录，我们表明 PEA 通过激活 GPR55 受体调节抑制性突触传递，从而促进 GABA 能自发性抑制性突触后电流（sIPSC）频率的短暂增加。随后 sIPSC 频率的衰减效应是由于内源性大麻素 2-AG 对突触前大麻素 CB1 受体（CB1R）的延迟刺激引起的，2-AG 的合成是由 PEA 在突触后神经元上刺激的。我们的结果表明，PEA 通过 GPR55 作用增强纹状体中的 GABA 传递，并在突触后位点触发 2-AG 的平行合成，2-AG 反过来通过刺激突触前 CB1R 以逆行方式抑制 GABA 释放。这项电生理学研究确定了 PEA 和 GPR55 的先前未被认识到的功能，表明 GABA 能传递受该化合物的控制，并揭示 PEA 调节内源性大麻素 2-AG 的释放。
