title: Metabotropic glutamate receptor 5/Homer interactions underlie stress effects on fear.
abstract: BACKGROUND
  Glutamatergic transmission is one of the main components of the stress response; nevertheless, its role in the emotional stress sequelae is not known. Here, we investigated whether interactions between group I metabotropic glutamate receptors (metabotropic glutamate receptor 1 and metabotropic glutamate receptor 5 [mGluR5]) and Homer proteins mediate the delayed and persistent enhancement of fear induced by acute stress.
  
  
  METHODS
  Antagonists and inverse agonists of metabotropic glutamate receptor 1 and mGluR5 were injected into the hippocampus after immobilization stress and before contextual fear conditioning. Metabotropic glutamate receptor 5 was displaced from constitutive Homer scaffolds by viral transfection of Homer1a or injection of Tat decoy peptides. The effects of these manipulations on stress-enhanced fear were determined.
  
  
  RESULTS
  We show that stress induces interactions between hippocampal mGluR5 and Homer1a; causes a sustained, ligand-independent mGluR5 activity; and enhances contextual fear. Consistent with this mechanism, enhancement of fear was abolished by delayed poststress application of inverse agonists, but not antagonists, of mGluR5. The effect of stress was mimicked by virally transfected Homer1a or injection of Tat-metabotropic glutamate receptor C-tail decoy peptides into the hippocampus.
  
  
  CONCLUSIONS
  Constitutive activation of mGluR5 is identified as a principal hippocampal mechanism underlying the delayed stress effects on emotion and memory. Inverse agonists, but not antagonists, of mGluR5 are therefore proposed as a preventive treatment option for acute and posttraumatic stress disorders.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, The Asher Center for Study and Treatment of Depressive Disorders, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Natalie C
authors.initials: NC
authors.lastname: Tronson
authors.forename: Yomayra F
authors.initials: YF
authors.lastname: Guzman
authors.forename: Anita L
authors.initials: AL
authors.lastname: Guedea
authors.forename: Kyu Hwan
authors.initials: KH
authors.lastname: Huh
authors.forename: Can
authors.initials: C
authors.lastname: Gao
authors.forename: Martin K
authors.initials: MK
authors.lastname: Schwarz
authors.forename: Jelena
authors.initials: J
authors.lastname: Radulovic
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001245:Association Learning / Q000502:physiology; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D003213:Conditioning, Psychological / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005239:Fear / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D000072233:Homer Scaffolding Proteins; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000502:physiology*; D013315:Stress, Psychological / Q000378:metabolism / Q000503:physiopathology*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C541428:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)piperidine; D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D000072233:Homer Scaffolding Proteins; D010880:Piperidines; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C121465:6-methyl-2-(phenylethynyl)pyridine