Diacylglycerol lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling

Endocannabinoids are small signaling lipids, with 2-arachidonoylglycerol (2-AG) implicated in modulating axonal growth and synaptic plasticity. The concept of short-range extracellular signaling by endocannabinoids is supported by the lack of trans-synaptic 2-AG signaling in mice lacking sn-1-diacyl...

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Main Authors:	Keimpema, Erik, Alpár, Alán, Howell, Fiona, Malenczyk, Katarzyna, Hobbs, Carl, Hurd, Yasmin L., Watanabe, Masahiko, Sakimura, Kenji, Kano, Masanobu, Doherty, Patrick, Harkany, Tibor
Format:	Online
Language:	English
Published:	Nature Publishing Group 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695556/

id	pubmed-3695556
recordtype	oai_dc
spelling	pubmed-36955562013-06-28 Diacylglycerol lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling Keimpema, Erik Alpár, Alán Howell, Fiona Malenczyk, Katarzyna Hobbs, Carl Hurd, Yasmin L. Watanabe, Masahiko Sakimura, Kenji Kano, Masanobu Doherty, Patrick Harkany, Tibor Article Endocannabinoids are small signaling lipids, with 2-arachidonoylglycerol (2-AG) implicated in modulating axonal growth and synaptic plasticity. The concept of short-range extracellular signaling by endocannabinoids is supported by the lack of trans-synaptic 2-AG signaling in mice lacking sn-1-diacylglycerol lipases (DAGLs), synthesizing 2-AG. Nevertheless, how far endocannabinoids can spread extracellularly to evoke physiological responses at CB1 cannabinoid receptors (CB1Rs) remains poorly understood. Here, we first show that cholinergic innervation of CA1 pyramidal cells of the hippocampus is sensitive to the genetic disruption of 2-AG signaling in DAGLα null mice. Next, we exploit a hybrid COS-7-cholinergic neuron co-culture system to demonstrate that heterologous DAGLα overexpression spherically excludes cholinergic growth cones from 2-AG-rich extracellular environments, and minimizes cell-cell contact in vitro. CB1R-mediated exclusion responses lasted 3 days, indicating sustained spherical 2-AG availability. Overall, these data suggest that extracellular 2-AG concentrations can be sufficient to activate CB1Rs along discrete spherical boundaries to modulate neuronal responsiveness. Nature Publishing Group 2013-06-28 /pmc/articles/PMC3695556/ /pubmed/23806960 http://dx.doi.org/10.1038/srep02093 Text en Copyright © 2013, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Keimpema, Erik Alpár, Alán Howell, Fiona Malenczyk, Katarzyna Hobbs, Carl Hurd, Yasmin L. Watanabe, Masahiko Sakimura, Kenji Kano, Masanobu Doherty, Patrick Harkany, Tibor
spellingShingle	Keimpema, Erik Alpár, Alán Howell, Fiona Malenczyk, Katarzyna Hobbs, Carl Hurd, Yasmin L. Watanabe, Masahiko Sakimura, Kenji Kano, Masanobu Doherty, Patrick Harkany, Tibor Diacylglycerol lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling
author_facet	Keimpema, Erik Alpár, Alán Howell, Fiona Malenczyk, Katarzyna Hobbs, Carl Hurd, Yasmin L. Watanabe, Masahiko Sakimura, Kenji Kano, Masanobu Doherty, Patrick Harkany, Tibor
author_sort	Keimpema, Erik
title	Diacylglycerol lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling
title_short	Diacylglycerol lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling
title_full	Diacylglycerol lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling
title_fullStr	Diacylglycerol lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling
title_full_unstemmed	Diacylglycerol lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling
title_sort	diacylglycerol lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling
description	Endocannabinoids are small signaling lipids, with 2-arachidonoylglycerol (2-AG) implicated in modulating axonal growth and synaptic plasticity. The concept of short-range extracellular signaling by endocannabinoids is supported by the lack of trans-synaptic 2-AG signaling in mice lacking sn-1-diacylglycerol lipases (DAGLs), synthesizing 2-AG. Nevertheless, how far endocannabinoids can spread extracellularly to evoke physiological responses at CB1 cannabinoid receptors (CB1Rs) remains poorly understood. Here, we first show that cholinergic innervation of CA1 pyramidal cells of the hippocampus is sensitive to the genetic disruption of 2-AG signaling in DAGLα null mice. Next, we exploit a hybrid COS-7-cholinergic neuron co-culture system to demonstrate that heterologous DAGLα overexpression spherically excludes cholinergic growth cones from 2-AG-rich extracellular environments, and minimizes cell-cell contact in vitro. CB1R-mediated exclusion responses lasted 3 days, indicating sustained spherical 2-AG availability. Overall, these data suggest that extracellular 2-AG concentrations can be sufficient to activate CB1Rs along discrete spherical boundaries to modulate neuronal responsiveness.
publisher	Nature Publishing Group
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3695556/
_version_	1611990301821370368

Diacylglycerol lipase α manipulation reveals developmental roles for intercellular endocannabinoid signaling

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