Cannabinoid type 2 receptors mediate a cell type-specific self-inhibition in cortical neurons

NEUROPHARMACOLOGY

卷:139

Article

Stumpf, Alexander¹  Parthier, Daniel¹  Sammons, Rosanna P.¹  Stempel, A. Vanessa^1,2  Breustedt, Joerg¹  Rost, Benjamin R.^1,3  Schmitz, Dietmar^1,3,4,5,6,7 

[1] Charite Univ Med Berlin, Neurosci Res Ctr, Berlin, Germany

[2] UCL, Sainsbury Wellcome Ctr Neural Circuits & Behav, London, England

[3] German Ctr Neurodegenerat Dis DZNE, Berlin, Germany

[4] Berlin Inst Hlth, Berlin, Germany

[5] Bernstein Ctr Computat Neurosci Berlin, Berlin, Germany

[6] Cluster Excellence NeuroCure, Berlin, Germany

[7] Einstein Ctr Neurosci, Berlin, Germany

关键词: Cannabinoid Receptor type 2;    Electrophysiology;    Endocannabinoids;    Somatosensory cortex;    Slow self-inhibition;   

DOI  :  10.1016/j.neuropharm.2018.07.020

来源: Elsevier

【 摘 要 】

Endogenous cannabinoids are diffusible lipid ligands of the main cannabinoid receptors type 1 and 2 (CB1R and CB2R). In the central nervous system endocannabinoids are produced in an activity-dependent manner and have been identified as retrograde modulators of synaptic transmission. Additionally, some neurons display a cell-autonomous slow self-inhibition (SSI) mediated by endocannabinoids. In these neurons, repetitive action potential firing triggers the production of endocannabinoids, which induce a long-lasting hyperpolarization of the membrane potential, rendering the cells less excitable. Different endocannabinoid receptors and effector mechanisms have been described underlying SSI in different cell types and brain areas. Here, we investigate SSI in neurons of layer 2/3 in the somatosensory cortex. High frequency bursts of action potentials induced SSI in pyramidal cells (PC) and regular spiking non pyramidal cells (RSNPC), but not in fast-spiking interneurons (FS). In RSNPCs the hyperpolarization was accompanied by a change in input resistance due to the activation of G protein-coupled inward rectifying K+ (GIRK) channels. A CB2R-specific agonist induced the long-lasting hyperpolarization, whereas preincubation with a CB2R-specific inverse agonist suppressed SSI. Additionally, using cannabinoid receptor knockout mice, we found that SSI was still intact in CB1R-deficient but abolished in CB2R-deficient mice. Taken together, we describe an additional SSI mechanism in which the activity-induced release of endocannabinoids activates GIRK channels via CB(2)Rs. These findings expand our knowledge about cell type-specific differential neuronal cannabinoid receptor signaling and suggest CB2R-selective compounds as potential therapeutic approaches. (C) 2018 Elsevier Ltd. All rights reserved.

【 授权许可】

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