CD44 Deficiency Is Associated with Increased Susceptibility to Stress-Induced Anxiety-like Behavior in Mice.
CD44 is a cell surface adhesion molecule and its principal ligand is hyaluronic acid (HA), a key component of the brain's extracellular matrix. CD44 levels are decreased in the cerebrospinal fluid (CSF) of depressed individuals, and the CD44 gene has been identified in genome wide association study as a possible risk gene in suicidal behavior. In order to define the pathobiological mechanisms by which CD44 may affect behavior, we investigated the role of CD44 using male CD44 knockout (CD44KO) and wild-type mice that underwent chronic mild stress (CMS). Behavior was characterized using the sucrose preference and forced swim tests, open field, novel object recognition, social preference, and the elevated plus maze tests. Gene expression in hippocampus was evaluated using quantitative real-time PCR. Brain monoamines and their metabolites were assessed by high-performance liquid chromatography and serum HA and IL-1β levels were measured using ELISA and electrochemiluminescence assays. CD44KO mice were more susceptible to stress-induced anxiety-like behavior and displayed increased anhedonia and despair than the wild-type controls. The behavioral phenotype of stressed CD44KO mice was associated with reduced cortical serotonergic and striatal dopaminergic turnover. The hippocampal expression of the receptor for HA-mediated motility (RHAMM) was reduced in the non- stressed CD44KO mice compared with WT mice, in a value similar to that observed in WT mice following exposure to stress. Taken together, our experiments suggest that CD44 plays a key role in stress response in mice.
Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, 49100, Petach-Tikva, Israel. barzilyr@post.tau.ac.il.|Geha Mental Health Center, Research Unit, Petach-Tikva, Israel. barzilyr@post.tau.ac.il.
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Barzilay
Division of Psychiatry, Department of Clinical Sciences, Lund University, Lund, Sweden.
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Ventorp
Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, 49100, Petach-Tikva, Israel.
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Segal-Gavish
Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, 49100, Petach-Tikva, Israel.
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Aharony
Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, 49100, Petach-Tikva, Israel.
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Bieber
Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, 49100, Petach-Tikva, Israel.
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Dar
Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, 49100, Petach-Tikva, Israel.
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Vescan
Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, 49100, Petach-Tikva, Israel.
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Globus
Geha Mental Health Center, Research Unit, Petach-Tikva, Israel.|Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, Petach-Tikva, Israel.
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Weizman
Lautenberg Center for Immunology, The Hebrew University, Jerusalem, Israel.
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Naor
Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, USA.
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Lipton
Division of Psychiatry, Department of Clinical Sciences, Lund University, Lund, Sweden.
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Janelidze
Division of Psychiatry, Department of Clinical Sciences, Lund University, Lund, Sweden.|Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
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Brundin
Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, 49100, Petach-Tikva, Israel.
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Offen
D000818:Animals; D001007:Anxiety / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D017353:Gene Deletion; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D018960:Hyaluronan Receptors / Q000235:genetics*; D006820:Hyaluronic Acid / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D010641:Phenotype; D012701:Serotonin / Q000378:metabolism; D013315:Stress, Psychological / Q000150:complications / Q000235:genetics* / Q000378:metabolism
D018960:Hyaluronan Receptors; D053583:Interleukin-1beta; D012701:Serotonin; D006820:Hyaluronic Acid; D004298:Dopamine
Animal model; Anxiety; CD44; Extracellular matrix; Hyaluronic acid; Stress