title: Addressing sufficiency of the CB1 receptor for endocannabinoid-mediated functions through conditional genetic rescue in forebrain GABAergic neurons.
abstract: 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.
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128, Mainz, Germany. remmersf@uni-mainz.de.
authors.forename: Floortje
authors.identifier: http://orcid.org/0000-0002-8436-0606
authors.initials: F
authors.lastname: Remmers
authors.affiliation: Institute of Physiology I, Westfaelische Wilhelms-University, 48149, Muenster, Germany.
authors.forename: Maren D
authors.initials: MD
authors.lastname: Lange
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128, Mainz, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Hamann
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128, Mainz, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Ruehle
authors.affiliation: Institute of Physiology I, Westfaelische Wilhelms-University, 48149, Muenster, Germany.
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Pape
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University Mainz, 55128, Mainz, Germany.
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
mesh_terms: D000679:Amygdala / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001007:Anxiety; D001522:Behavior, Animal; D005108:Extinction, Psychological; D005239:Fear; D059330:GABAergic Neurons / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D053444:Inhibitory Postsynaptic Potentials; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016548:Prosencephalon / Q000502:physiology*; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced
chemical_list: D043884:Receptor, Cannabinoid, CB1
keywords: Anxiety; Endocannabinoid; Fear extinction; GABA; Seizure susceptibility