title: Homer1/mGluR5 activity moderates vulnerability to chronic social stress.
abstract: Stress-induced psychiatric disorders, such as depression, have recently been linked to changes in glutamate transmission in the central nervous system. Glutamate signaling is mediated by a range of receptors, including metabotropic glutamate receptors (mGluRs). In particular, mGluR subtype 5 (mGluR5) is highly implicated in stress-induced psychopathology. The major scaffold protein Homer1 critically interacts with mGluR5 and has also been linked to several psychopathologies. Yet, the specific role of Homer1 in this context remains poorly understood. We used chronic social defeat stress as an established animal model of depression and investigated changes in transcription of Homer1a and Homer1b/c isoforms and functional coupling of Homer1 to mGluR5. Next, we investigated the consequences of Homer1 deletion, overexpression of Homer1a, and chronic administration of the mGluR5 inverse agonist CTEP (2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine) on the effects of chronic stress. In mice exposed to chronic stress, Homer1b/c, but not Homer1a, mRNA was upregulated and, accordingly, Homer1/mGluR5 coupling was disrupted. We found a marked hyperactivity behavior as well as a dysregulated hypothalamic-pituitary-adrenal axis activity in chronically stressed Homer1 knockout (KO) mice. Chronic administration of the selective and orally bioavailable mGluR5 inverse agonist, CTEP, was able to recover behavioral alterations induced by chronic stress, whereas overexpression of Homer1a in the hippocampus led to an increased vulnerability to chronic stress, reflected in an increased physiological response to stress as well as enhanced depression-like behavior. Overall, our results implicate the glutamatergic system in the emergence of stress-induced psychiatric disorders, and support the Homer1/mGluR5 complex as a target for the development of novel antidepressant agents.
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Klaus V
authors.initials: KV
authors.lastname: Wagner
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Jakob
authors.initials: J
authors.lastname: Hartmann
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Christiana
authors.initials: C
authors.lastname: Labermaier
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Häusl
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Gengjing
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Harbich
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Bianca
authors.initials: B
authors.lastname: Schmid
authors.affiliation: Department of Neurobiology, Key Laboratory of Medical Neurobiology of Ministry of Health of China, Zhejiang Province Key Laboratory of Neurobiology, Zhejiang University School of Medicine, Hangzhou, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Wang
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Santarelli
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Kohl
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Nils C
authors.initials: NC
authors.lastname: Gassen
authors.affiliation: 1] Faculty of Science, Medicine and Health and Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia [2] Schizophrenia Research Institute, Sydney NSW, Australia.
authors.forename: Natalie
authors.initials: N
authors.lastname: Matosin
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Schieven
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Webhofer
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Turck
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology, and Rare Diseases Translational Area (NORD), Basel, Switzerland.
authors.forename: Lothar
authors.initials: L
authors.lastname: Lindemann
authors.affiliation: Roche Pharmaceutical Research and Early Development, Discovery Chemistry, Basel, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Jaschke
authors.affiliation: Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology, and Rare Diseases Translational Area (NORD), Basel, Switzerland.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Wettstein
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Theo
authors.initials: T
authors.lastname: Rein
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Marianne B
authors.initials: MB
authors.lastname: Müller
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Mathias V
authors.initials: MV
authors.lastname: Schmidt
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D003866:Depressive Disorder / Q000378:metabolism*; D004195:Disease Models, Animal; D004291:Dominance-Subordination; D054314:Drug Inverse Agonism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D000072233:Homer Scaffolding Proteins; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020033:Protein Isoforms; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055500:Resilience, Psychological / Q000187:drug effects; D013315:Stress, Psychological / Q000378:metabolism*
chemical_list: C569289:2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine; D002352:Carrier Proteins; D018691:Excitatory Amino Acid Antagonists; C578936:Grm5 protein, mouse; D000072233:Homer Scaffolding Proteins; C000606623:Homer1 protein, mouse; D007093:Imidazoles; D020033:Protein Isoforms; D011725:Pyridines; D012333:RNA, Messenger; D064529:Receptor, Metabotropic Glutamate 5