Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress

• DOI: 10.1038/npp.2014.308
• Publication Date: 2014-11-20T11:56:58Z
• Authors: Klaus V Wagner; Jakob Hartmann; Christiana Laberm...; Alexander S Häusl; Gengjing Zhao; Daniela Harbich; Bianca Schmid; Xiao-Dong Wang; Sara Santarelli; Christine Kohl; Nils C Gassen; Natalie Matosin; Marcel Schieven; Christian Webhofer; Christoph W Turck; Lothar Lindemann; Georg Jaschke; Joseph G Wettstein; Theo Rein; Marianne B Müller; Mathias V Schmidt
• Keywords: Dominance-Subordination; Male; 572; Drug Inverse Agonism; Pyridines; Receptor, Metabotropic Glutamate 5; Mice; 03 medical and health sciences; Homer Scaffolding Proteins; Medicine and Health Sciences; Animals; Protein Isoforms; RNA, Messenger; Mice, Knockout; Depressive Disorder; 0303 health sciences; Imidazoles; Brain; Resilience, Psychological; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Chronic Disease; Carrier Proteins; Excitatory Amino Acid Antagonists

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.