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CD44 Deficiency Is Associated with Increased Susceptibility to Stress-Induced Anxiety-like Behavior in Mice
R Barzilay1,2, F Ventorp3, H Segal-Gavish4
1Laboratory of Neuroscience, Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel Aviv University, 49100, Petach-Tikva, Israel. barzilyr@post.tau.ac.il.
Insights
Mice lacking CD44, a cell surface molecule, showed increased susceptibility to stress-induced anxiety, anhedonia, and despair. This suggests CD44 plays a crucial role in the mouse stress response.
Area of Science:
- Neuroscience
- Molecular Biology
- Behavioral Science
Background:
- CD44, a cell surface adhesion molecule binding hyaluronic acid (HA), is implicated in behavior.
- Reduced CD44 in cerebrospinal fluid (CSF) and its gene's association with suicidal behavior suggest a role in mood disorders.
- Understanding CD44's function is crucial for defining its role in stress and behavior.
Purpose of the Study:
- To investigate the role of CD44 in stress response and associated behaviors.
- To elucidate the pathobiological mechanisms linking CD44 to behavioral changes under stress.
Main Methods:
- Utilized male CD44 knockout (CD44KO) and wild-type mice subjected to chronic mild stress (CMS).
- Assessed behavior via sucrose preference, forced swim, open field, novel object recognition, social preference, and elevated plus maze tests.
- Analyzed gene expression (RHAMM), brain monoamines, serum HA, and IL-1β levels.
Main Results:
- CD44KO mice exhibited heightened susceptibility to stress, displaying increased anxiety-like behavior, anhedonia, and despair compared to wild-type controls.
- Stressed CD44KO mice showed reduced serotonergic and dopaminergic turnover in the cortex and striatum, respectively.
- Reduced hippocampal RHAMM expression was observed in non-stressed CD44KO mice, mirroring stressed wild-type mice.
Conclusions:
- CD44 plays a significant role in modulating the behavioral and neurochemical responses to stress in mice.
- The absence of CD44 exacerbates stress-induced behavioral deficits, potentially through alterations in monoamine pathways and HA-mediated signaling.
- These findings highlight CD44 as a potential therapeutic target for stress-related disorders.
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.
