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Addressing sufficiency of the CB1 receptor for endocannabinoid-mediated functions through conditional genetic rescue in forebrain GABAergic neurons

Genetic inactivation of the cannabinoid CB1 receptor gene in different cell types in the brain has previously revealed necessary functions for distinct synaptic plasticity processes and behaviors. Here, we sought to identify CB1 receptor expression sites that are minimally required to reconstruct no...

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Autores principales: Remmers, Floortje, Lange, Maren D., Hamann, Martina, Ruehle, Sabine, Pape, Hans-Christian, Lutz, Beat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676814/
https://www.ncbi.nlm.nih.gov/pubmed/28393261
http://dx.doi.org/10.1007/s00429-017-1411-5
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author Remmers, Floortje
Lange, Maren D.
Hamann, Martina
Ruehle, Sabine
Pape, Hans-Christian
Lutz, Beat
author_facet Remmers, Floortje
Lange, Maren D.
Hamann, Martina
Ruehle, Sabine
Pape, Hans-Christian
Lutz, Beat
author_sort Remmers, Floortje
collection PubMed
description Genetic inactivation of the cannabinoid CB1 receptor gene in different cell types in the brain has previously revealed necessary functions for distinct synaptic plasticity processes and behaviors. Here, we sought to identify CB1 receptor expression sites that are minimally required to reconstruct normal phenotypes. In a CB1-null background, we re-expressed endogenous CB1 receptors in forebrain GABAergic neurons, thereby assessing the sufficiency of CB1 receptors. Depolarization-induced suppression of inhibitory, but not excitatory, transmission was restored in hippocampal and amygdalar circuits. GABAergic CB1 receptors did not convey protection against chemically induced seizures, but prevented the spontaneous mortality observed in CB1 null mutants. Rescue of GABAergic CB1 receptors largely restored normal anxiety-like behavior but improved extinction of learned fear only marginally. This study illustrates that the approach of genetic reconstruction of complex behaviors is feasible. It also revealed distinct degrees of modulation for different emotional behaviors by the GABAergic population of CB1 receptors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00429-017-1411-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-56768142017-11-21 Addressing sufficiency of the CB1 receptor for endocannabinoid-mediated functions through conditional genetic rescue in forebrain GABAergic neurons Remmers, Floortje Lange, Maren D. Hamann, Martina Ruehle, Sabine Pape, Hans-Christian Lutz, Beat Brain Struct Funct Original Article Genetic inactivation of the cannabinoid CB1 receptor gene in different cell types in the brain has previously revealed necessary functions for distinct synaptic plasticity processes and behaviors. Here, we sought to identify CB1 receptor expression sites that are minimally required to reconstruct normal phenotypes. In a CB1-null background, we re-expressed endogenous CB1 receptors in forebrain GABAergic neurons, thereby assessing the sufficiency of CB1 receptors. Depolarization-induced suppression of inhibitory, but not excitatory, transmission was restored in hippocampal and amygdalar circuits. GABAergic CB1 receptors did not convey protection against chemically induced seizures, but prevented the spontaneous mortality observed in CB1 null mutants. Rescue of GABAergic CB1 receptors largely restored normal anxiety-like behavior but improved extinction of learned fear only marginally. This study illustrates that the approach of genetic reconstruction of complex behaviors is feasible. It also revealed distinct degrees of modulation for different emotional behaviors by the GABAergic population of CB1 receptors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00429-017-1411-5) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2017-04-09 2017 /pmc/articles/PMC5676814/ /pubmed/28393261 http://dx.doi.org/10.1007/s00429-017-1411-5 Text en © The Author(s) 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Remmers, Floortje
Lange, Maren D.
Hamann, Martina
Ruehle, Sabine
Pape, Hans-Christian
Lutz, Beat
Addressing sufficiency of the CB1 receptor for endocannabinoid-mediated functions through conditional genetic rescue in forebrain GABAergic neurons
title Addressing sufficiency of the CB1 receptor for endocannabinoid-mediated functions through conditional genetic rescue in forebrain GABAergic neurons
title_full Addressing sufficiency of the CB1 receptor for endocannabinoid-mediated functions through conditional genetic rescue in forebrain GABAergic neurons
title_fullStr Addressing sufficiency of the CB1 receptor for endocannabinoid-mediated functions through conditional genetic rescue in forebrain GABAergic neurons
title_full_unstemmed Addressing sufficiency of the CB1 receptor for endocannabinoid-mediated functions through conditional genetic rescue in forebrain GABAergic neurons
title_short Addressing sufficiency of the CB1 receptor for endocannabinoid-mediated functions through conditional genetic rescue in forebrain GABAergic neurons
title_sort addressing sufficiency of the cb1 receptor for endocannabinoid-mediated functions through conditional genetic rescue in forebrain gabaergic neurons
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676814/
https://www.ncbi.nlm.nih.gov/pubmed/28393261
http://dx.doi.org/10.1007/s00429-017-1411-5
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