Abstract
Proper myelination of axons is crucial for normal sensory, motor, and cognitive function. Abnormal myelination is seen in brain disorders such as major depressive disorder (MDD), but the molecular mechanisms connecting demyelination with the pathobiology remain largely unknown. We observed demyelination and synaptic deficits in mice exposed to either chronic, unpredictable mild stress (CUMS) or LPS, 2 paradigms for inducing depression-like states. Pharmacological restoration of myelination normalized both synaptic deficits and depression-related behaviors. Furthermore, we found increased ephrin A4 receptor (EphA4) expression in the excitatory neurons of mice subjected to CUMS, and shRNA knockdown of EphA4 prevented demyelination and depression-like behaviors. These animal data are consistent with the decrease in myelin basic protein and the increase in EphA4 levels we observed in postmortem brain samples from patients with MDD. Our results provide insights into the etiology of depressive symptoms in some patients and suggest that inhibition of EphA4 or the promotion of myelination could be a promising strategy for treating depression.
Highlights
Major depressive disorder (MDD) is a very common and severe psychiatric disorder that affects approximately 300 million people worldwide [1], with a mortality rate of up to 6%, usually by suicide [2]
Our experiments demonstrate that ephrin A4 receptor (EphA4) is necessary for the demyelination and synaptic deficits seen in animal models for the study of depression, and this observation is supported by convergent observational data from human brain tissue samples
We found significantly decreased myelin basic protein (MBP) levels in the hippocampus of mice subjected to CUMS compared with the levels in control animals (Figure 1, A–C)
Summary
Major depressive disorder (MDD) is a very common and severe psychiatric disorder that affects approximately 300 million people worldwide [1], with a mortality rate of up to 6%, usually by suicide [2]. Electroconvulsive therapy is an old but highly effective treatment for depression that has very significant side effects [9], and emerging treatments such as ketamine [10] and other brain stimulation techniques require further validation [11, 12]. Emerging in vivo neuroimaging studies have shown that patients with MDD have abnormal white matter and myelin structure in multiple brain regions, including the dorsolateral prefrontal cortex, the anterior cingulate cortex, the hippocampus, and the corpus callosum [17–19].
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