Abstract
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.
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Acknowledgments
This study was supported by grants from Michigan State University (LB), the Swedish Research Council (VR) nos. 2009-4284 and 2011-4787 (LB), 2002-5297 and 2008-2922 (LT-B), 2009-7052 and 2011-4795 (SE), the Province of Scania clinical state grants (ALF, for LB and LT-B); and in part by the Udall Center of Excellence in Parkinson’s Disease Research at Michigan State University, P50NS58830 (JWL). The funding source had no further role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
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R. Barzilay and F. Ventorp contributed equally to the study.
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Barzilay, R., Ventorp, F., Segal-Gavish, H. et al. CD44 Deficiency Is Associated with Increased Susceptibility to Stress-Induced Anxiety-like Behavior in Mice. J Mol Neurosci 60, 548–558 (2016). https://doi.org/10.1007/s12031-016-0835-3
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DOI: https://doi.org/10.1007/s12031-016-0835-3