title: Impaired 2-AG Signaling in Hippocampal Glutamatergic Neurons: Aggravation of Anxiety-Like Behavior and Unaltered Seizure Susceptibility.
abstract: BACKGROUND
  Postsynaptically generated 2-arachidonoylglycerol activates the presynaptic cannabinoid type-1 receptor, which is involved in synaptic plasticity at both glutamatergic and GABAergic synapses. However, the differential function of 2-arachidonoylglycerol signaling at glutamatergic vs GABAergic synapses in the context of animal behavior has not been investigated yet.
  
  
  METHODS
  Here, we analyzed the role of 2-arachidonoylglycerol signaling selectively in hippocampal glutamatergic neurons. Monoacylglycerol lipase, the primary degrading enzyme of 2-arachidonoylglycerol, is expressed at presynaptic sites of excitatory and inhibitory neurons. By adeno-associated virus-mediated overexpression of monoacylglycerol lipase in glutamatergic neurons of the mouse hippocampus, we selectively interfered with 2-arachidonoylglycerol signaling at glutamatergic synapses of these neurons.
  
  
  RESULTS
  Genetic modification of monoacylglycerol lipase resulted in a 50% decrease in 2-arachidonoylglycerol tissue levels without affecting the content of the second major endocannabinoid anandamide. A typical electrophysiological read-out for 2-arachidonoylglycerol signaling is the depolarization-induced suppression of excitation and of inhibition. Elevated monoacylglycerol lipase levels at glutamatergic terminals selectively impaired depolarization-induced suppression of excitation, while depolarization-induced suppression of inhibition was not significantly changed. At the behavioral level, mice with impaired hippocampal glutamatergic 2-arachidonoylglycerol signaling exhibited increased anxiety-like behavior but showed no alterations in aversive memory formation and seizure susceptibility.
  
  
  CONCLUSIONS
  Our data indicate that 2-arachidonoylglycerol signaling selectively in hippocampal glutamatergic neurons is essential for the animal's adaptation to aversive situations.
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany (Dr Guggenhuber, Dr Bindila, Dr Leschik, Dr Lomazzo, Dr Remmers, Ms Zimmermann, Ms Lerner, Dr Klugmann, and Dr Lutz); Institute of Physiology I (Neurophysiology), Westfaelische Wilhelms-University, Muenster, Germany (Drs Romo-Parra and Pape); Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Kensington Campus, Sydney, NSW, Australia (Dr Klugmann).
authors.forename: Stephan
authors.initials: S
authors.lastname: Guggenhuber
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany (Dr Guggenhuber, Dr Bindila, Dr Leschik, Dr Lomazzo, Dr Remmers, Ms Zimmermann, Ms Lerner, Dr Klugmann, and Dr Lutz); Institute of Physiology I (Neurophysiology), Westfaelische Wilhelms-University, Muenster, Germany (Drs Romo-Parra and Pape); Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Kensington Campus, Sydney, NSW, Australia (Dr Klugmann).
authors.forename: Hector
authors.initials: H
authors.lastname: Romo-Parra
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany (Dr Guggenhuber, Dr Bindila, Dr Leschik, Dr Lomazzo, Dr Remmers, Ms Zimmermann, Ms Lerner, Dr Klugmann, and Dr Lutz); Institute of Physiology I (Neurophysiology), Westfaelische Wilhelms-University, Muenster, Germany (Drs Romo-Parra and Pape); Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Kensington Campus, Sydney, NSW, Australia (Dr Klugmann).
authors.forename: Laura
authors.initials: L
authors.lastname: Bindila
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany (Dr Guggenhuber, Dr Bindila, Dr Leschik, Dr Lomazzo, Dr Remmers, Ms Zimmermann, Ms Lerner, Dr Klugmann, and Dr Lutz); Institute of Physiology I (Neurophysiology), Westfaelische Wilhelms-University, Muenster, Germany (Drs Romo-Parra and Pape); Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Kensington Campus, Sydney, NSW, Australia (Dr Klugmann).
authors.forename: Julia
authors.initials: J
authors.lastname: Leschik
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany (Dr Guggenhuber, Dr Bindila, Dr Leschik, Dr Lomazzo, Dr Remmers, Ms Zimmermann, Ms Lerner, Dr Klugmann, and Dr Lutz); Institute of Physiology I (Neurophysiology), Westfaelische Wilhelms-University, Muenster, Germany (Drs Romo-Parra and Pape); Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Kensington Campus, Sydney, NSW, Australia (Dr Klugmann).
authors.forename: Ermelinda
authors.initials: E
authors.lastname: Lomazzo
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany (Dr Guggenhuber, Dr Bindila, Dr Leschik, Dr Lomazzo, Dr Remmers, Ms Zimmermann, Ms Lerner, Dr Klugmann, and Dr Lutz); Institute of Physiology I (Neurophysiology), Westfaelische Wilhelms-University, Muenster, Germany (Drs Romo-Parra and Pape); Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Kensington Campus, Sydney, NSW, Australia (Dr Klugmann).
authors.forename: Floortje
authors.initials: F
authors.lastname: Remmers
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany (Dr Guggenhuber, Dr Bindila, Dr Leschik, Dr Lomazzo, Dr Remmers, Ms Zimmermann, Ms Lerner, Dr Klugmann, and Dr Lutz); Institute of Physiology I (Neurophysiology), Westfaelische Wilhelms-University, Muenster, Germany (Drs Romo-Parra and Pape); Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Kensington Campus, Sydney, NSW, Australia (Dr Klugmann).
authors.forename: Tina
authors.initials: T
authors.lastname: Zimmermann
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany (Dr Guggenhuber, Dr Bindila, Dr Leschik, Dr Lomazzo, Dr Remmers, Ms Zimmermann, Ms Lerner, Dr Klugmann, and Dr Lutz); Institute of Physiology I (Neurophysiology), Westfaelische Wilhelms-University, Muenster, Germany (Drs Romo-Parra and Pape); Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Kensington Campus, Sydney, NSW, Australia (Dr Klugmann).
authors.forename: Raissa
authors.initials: R
authors.lastname: Lerner
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany (Dr Guggenhuber, Dr Bindila, Dr Leschik, Dr Lomazzo, Dr Remmers, Ms Zimmermann, Ms Lerner, Dr Klugmann, and Dr Lutz); Institute of Physiology I (Neurophysiology), Westfaelische Wilhelms-University, Muenster, Germany (Drs Romo-Parra and Pape); Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Kensington Campus, Sydney, NSW, Australia (Dr Klugmann).
authors.forename: Matthias
authors.initials: M
authors.lastname: Klugmann
authors.affiliation: Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany (Dr Guggenhuber, Dr Bindila, Dr Leschik, Dr Lomazzo, Dr Remmers, Ms Zimmermann, Ms Lerner, Dr Klugmann, and Dr Lutz); Institute of Physiology I (Neurophysiology), Westfaelische Wilhelms-University, Muenster, Germany (Drs Romo-Parra and Pape); Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Kensington Campus, Sydney, NSW, Australia (Dr Klugmann).
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, Germany (Dr Guggenhuber, Dr Bindila, Dr Leschik, Dr Lomazzo, Dr Remmers, Ms Zimmermann, Ms Lerner, Dr Klugmann, and Dr Lutz); Institute of Physiology I (Neurophysiology), Westfaelische Wilhelms-University, Muenster, Germany (Drs Romo-Parra and Pape); Translational Neuroscience Facility, Department of Physiology, School of Medical Sciences, University of New South Wales, UNSW Kensington Campus, Sydney, NSW, Australia (Dr Klugmann). blutz@uni-mainz.de.
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000523:psychology; D001095:Arachidonic Acids / Q000378:metabolism*; D063388:Endocannabinoids / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D005989:Glycerides / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D012640:Seizures / Q000378:metabolism* / Q000523:psychology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D018698:Glutamic Acid; C094503:glyceryl 2-arachidonate
keywords: Monoacylglycerol lipase; anxiety; endocannabinoids; epilepsy; hippocampus