title: Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation.
abstract: Endocannabinoid (eCB) signaling has been heavily implicated in the modulation of anxiety and depressive behaviors and emotional learning. However, the role of the most-abundant endocannabinoid 2-arachidonoylglycerol (2-AG) in the physiological regulation of affective behaviors is not well understood. Here, we show that genetic deletion of the 2-AG synthetic enzyme diacylglycerol lipase α (DAGLα) in mice reduces brain, but not circulating, 2-AG levels. DAGLα deletion also results in anxiety-like and sex-specific anhedonic phenotypes associated with impaired activity-dependent eCB retrograde signaling at amygdala glutamatergic synapses. Importantly, acute pharmacological normalization of 2-AG levels reverses both phenotypes of DAGLα-deficient mice. These data suggest 2-AG deficiency could contribute to the pathogenesis of affective disorders and that pharmacological normalization of 2-AG signaling could represent an approach for the treatment of mood and anxiety disorders.
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Shonesy
authors.affiliation: Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Bluett
authors.affiliation: Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Teniel S
authors.initials: TS
authors.lastname: Ramikie
authors.affiliation: Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Báldi
authors.affiliation: Departments of Biochemistry, Chemistry, and Pharmacology, A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Hermanson
authors.affiliation: Departments of Biochemistry, Chemistry, and Pharmacology, A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Kingsley
authors.affiliation: Departments of Biochemistry, Chemistry, and Pharmacology, A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Marnett
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt-Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Danny G
authors.initials: DG
authors.lastname: Winder
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt-Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
authors.affiliation: Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Vanderbilt-Kennedy Center for Research on Human Development, Vanderbilt University School of Medicine, Nashville, TN 37232, USA. Electronic address: sachin.patel@vanderbilt.edu.
authors.forename: Sachin
authors.initials: S
authors.lastname: Patel
mesh_terms: D000679:Amygdala / Q000503:physiopathology; D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D001095:Arachidonic Acids / Q000096:biosynthesis*; D003863:Depression / Q000378:metabolism; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000096:biosynthesis*; D005260:Female; D018698:Glutamic Acid / Q000502:physiology; D005989:Glycerides / Q000096:biosynthesis*; D008297:Male; D018345:Mice, Knockout; D009435:Synaptic Transmission
chemical_list: D001095:Arachidonic Acids; D063388:Endocannabinoids; D005989:Glycerides; D018698:Glutamic Acid; C094503:glyceryl 2-arachidonate