Skip to main content

Main menu

  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE

User menu

  • Log in
  • My Cart

Search

  • Advanced search
Journal of Neuroscience
  • Log in
  • My Cart
Journal of Neuroscience

Advanced Search

Submit a Manuscript
  • HOME
  • CONTENT
    • Early Release
    • Featured
    • Current Issue
    • Issue Archive
    • Collections
    • Podcast
  • ALERTS
  • FOR AUTHORS
    • Information for Authors
    • Fees
    • Journal Clubs
    • eLetters
    • Submit
  • EDITORIAL BOARD
  • ABOUT
    • Overview
    • Advertise
    • For the Media
    • Rights and Permissions
    • Privacy Policy
    • Feedback
  • SUBSCRIBE
PreviousNext
Articles, Cellular/Molecular

Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release

Sang-Hun Lee, Marco Ledri, Blanka Tóth, Ivan Marchionni, Christopher M. Henstridge, Barna Dudok, Kata Kenesei, László Barna, Szilárd I. Szabó, Tibor Renkecz, Michelle Oberoi, Masahiko Watanabe, Charles L. Limoli, George Horvai, Ivan Soltesz and István Katona
Journal of Neuroscience 8 July 2015, 35 (27) 10039-10057; DOI: https://doi.org/10.1523/JNEUROSCI.4112-14.2015
Sang-Hun Lee
1Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Sang-Hun Lee
Marco Ledri
2Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Blanka Tóth
3Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, H-1111 Budapest, Hungary,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ivan Marchionni
1Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christopher M. Henstridge
2Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Barna Dudok
2Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary,
4School of PhD Studies, Semmelweis University, H-1769 Budapest, Hungary,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Barna Dudok
Kata Kenesei
2Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
László Barna
2Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Szilárd I. Szabó
2Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Tibor Renkecz
3Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, H-1111 Budapest, Hungary,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michelle Oberoi
1Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Michelle Oberoi
Masahiko Watanabe
5Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Charles L. Limoli
7Department of Radiation Oncology, University of California, Irvine, California 92697
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
George Horvai
3Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, H-1111 Budapest, Hungary,
6MTA-BME Research Group of Technical Analytical Chemistry, H-1111 Budapest, Hungary, and
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ivan Soltesz
1Department of Anatomy and Neurobiology, University of California, Irvine, Irvine, California 92697,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
István Katona
2Momentum Laboratory of Molecular Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083 Budapest, Hungary,
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for István Katona
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

Persistent CB1 cannabinoid receptor activity limits neurotransmitter release at various synapses throughout the brain. However, it is not fully understood how constitutively active CB1 receptors, tonic endocannabinoid signaling, and its regulation by multiple serine hydrolases contribute to the synapse-specific calibration of neurotransmitter release probability. To address this question at perisomatic and dendritic GABAergic synapses in the mouse hippocampus, we used a combination of paired whole-cell patch-clamp recording, liquid chromatography/tandem mass spectrometry, stochastic optical reconstruction microscopy super-resolution imaging, and immunogold electron microscopy. Unexpectedly, application of the CB1 antagonist and inverse agonist AM251 [N-1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide], but not the neutral antagonist NESS0327 [8-chloro-1-(2,4-dichlorophenyl)-N-piperidin-1-yl-5,6-dihydro-4H-benzo[2,3]cyclohepta[2,4-b]pyrazole-3-carboxamine], significantly increased synaptic transmission between CB1-positive perisomatic interneurons and CA1 pyramidal neurons. JZL184 (4-nitrophenyl 4-[bis(1,3-benzodioxol-5-yl)(hydroxy)methyl]piperidine-1-carboxylate), a selective inhibitor of monoacylglycerol lipase (MGL), the presynaptic degrading enzyme of the endocannabinoid 2-arachidonoylglycerol (2-AG), elicited a robust increase in 2-AG levels and concomitantly decreased GABAergic transmission. In contrast, inhibition of fatty acid amide hydrolase (FAAH) by PF3845 (N-pyridin-3-yl-4-[[3-[5-(trifluoromethyl)pyridin-2-yl]oxyphenyl]methyl]piperidine-1-carboxamide) elevated endocannabinoid/endovanilloid anandamide levels but did not change GABAergic synaptic activity. However, FAAH inhibitors attenuated tonic 2-AG increase and also decreased its synaptic effects. This antagonistic interaction required the activation of the transient receptor potential vanilloid receptor TRPV1, which was concentrated on postsynaptic intracellular membrane cisternae at perisomatic GABAergic symmetrical synapses. Interestingly, neither AM251, JZL184, nor PF3845 affected CB1-positive dendritic interneuron synapses. Together, these findings are consistent with the possibility that constitutively active CB1 receptors substantially influence perisomatic GABA release probability and indicate that the synaptic effects of tonic 2-AG release are tightly controlled by presynaptic MGL activity and also by postsynaptic endovanilloid signaling and FAAH activity.

SIGNIFICANCE STATEMENT Tonic cannabinoid signaling plays a critical role in the regulation of synaptic transmission. However, the mechanistic details of how persistent CB1 cannabinoid receptor activity inhibits neurotransmitter release have remained elusive. Therefore, electrophysiological recordings, lipid measurements, and super-resolution imaging were combined to elucidate those signaling molecules and mechanisms that underlie tonic cannabinoid signaling. The findings indicate that constitutive CB1 activity has pivotal function in the tonic control of hippocampal GABA release. Moreover, the endocannabinoid 2-arachidonoylglycerol (2-AG) is continuously generated postsynaptically, but its synaptic effect is regulated strictly by presynaptic monoacylglycerol lipase activity. Finally, anandamide signaling antagonizes tonic 2-AG signaling via activation of postsynaptic transient receptor potential vanilloid TRPV1 receptors. This unexpected mechanistic diversity may be necessary to fine-tune GABA release probability under various physiological and pathophysiological conditions.

  • 2-arachidonoylglycerol
  • endocannabinod
  • GABA
  • hippocampus
  • interneuron
  • TRPV1

This article is freely available online through the J Neurosci Author Open Choice option.

View Full Text
Back to top

In this issue

The Journal of Neuroscience: 35 (27)
Journal of Neuroscience
Vol. 35, Issue 27
8 Jul 2015
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Advertising (PDF)
  • Ed Board (PDF)
Email

Thank you for sharing this Journal of Neuroscience article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release
(Your Name) has forwarded a page to you from Journal of Neuroscience
(Your Name) thought you would be interested in this article in Journal of Neuroscience.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
View Full Page PDF
Citation Tools
Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release
Sang-Hun Lee, Marco Ledri, Blanka Tóth, Ivan Marchionni, Christopher M. Henstridge, Barna Dudok, Kata Kenesei, László Barna, Szilárd I. Szabó, Tibor Renkecz, Michelle Oberoi, Masahiko Watanabe, Charles L. Limoli, George Horvai, Ivan Soltesz, István Katona
Journal of Neuroscience 8 July 2015, 35 (27) 10039-10057; DOI: 10.1523/JNEUROSCI.4112-14.2015

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Respond to this article
Request Permissions
Share
Multiple Forms of Endocannabinoid and Endovanilloid Signaling Regulate the Tonic Control of GABA Release
Sang-Hun Lee, Marco Ledri, Blanka Tóth, Ivan Marchionni, Christopher M. Henstridge, Barna Dudok, Kata Kenesei, László Barna, Szilárd I. Szabó, Tibor Renkecz, Michelle Oberoi, Masahiko Watanabe, Charles L. Limoli, George Horvai, Ivan Soltesz, István Katona
Journal of Neuroscience 8 July 2015, 35 (27) 10039-10057; DOI: 10.1523/JNEUROSCI.4112-14.2015
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Keywords

  • 2-arachidonoylglycerol
  • endocannabinod
  • GABA
  • hippocampus
  • interneuron
  • TRPV1

Responses to this article

Respond to this article

Jump to comment:

No eLetters have been published for this article.

Related Articles

Cited By...

More in this TOC Section

Articles

  • Choice Behavior Guided by Learned, But Not Innate, Taste Aversion Recruits the Orbitofrontal Cortex
  • Maturation of Spontaneous Firing Properties after Hearing Onset in Rat Auditory Nerve Fibers: Spontaneous Rates, Refractoriness, and Interfiber Correlations
  • Insulin Treatment Prevents Neuroinflammation and Neuronal Injury with Restored Neurobehavioral Function in Models of HIV/AIDS Neurodegeneration
Show more Articles

Cellular/Molecular

  • Cleavage of VAMP2/3 Affects Oligodendrocyte Lineage Development in the Developing Mouse Spinal Cord
  • P2Y6 receptor-dependent microglial phagocytosis of synapses during development regulates synapse density and memory
  • Acute ethanol modulates synaptic inhibition in the basolateral amygdala via rapid NLRP3 inflammasome activation and regulates anxiety-like behavior in rats
Show more Cellular/Molecular
  • Home
  • Alerts
  • Visit Society for Neuroscience on Facebook
  • Follow Society for Neuroscience on Twitter
  • Follow Society for Neuroscience on LinkedIn
  • Visit Society for Neuroscience on Youtube
  • Follow our RSS feeds

Content

  • Early Release
  • Current Issue
  • Issue Archive
  • Collections

Information

  • For Authors
  • For Advertisers
  • For the Media
  • For Subscribers

About

  • About the Journal
  • Editorial Board
  • Privacy Policy
  • Contact
(JNeurosci logo)
(SfN logo)

Copyright © 2023 by the Society for Neuroscience.
JNeurosci Online ISSN: 1529-2401

The ideas and opinions expressed in JNeurosci do not necessarily reflect those of SfN or the JNeurosci Editorial Board. Publication of an advertisement or other product mention in JNeurosci should not be construed as an endorsement of the manufacturer’s claims. SfN does not assume any responsibility for any injury and/or damage to persons or property arising from or related to any use of any material contained in JNeurosci.