The Eph receptor A4 plays a role in demyelination and depression-related behavior

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 lipopolysaccharide (LPS), two paradigms for inducing depression-like states.Pharmacologically restoring myelination normalized both synaptic deficits and depression-related behaviours. Furthermore, we found increased EphA4 expression in the excitatory neurons of CUMS mice and shRNA knockdown of EphA4 prevented demyelination and depression-like behaviours. These animal data are consistent with the decreased myelin basic protein and increased EphA4 levels we observed in postmortem brain from patients with MDD. Our results provide novel insights into the etiology of depressive symptoms in some patients and suggest that inhibiting EphA4 or promoting myelination could be a promising and novel strategy for treating depression.

A disintegrin and metalloproteinase 10 (ADAM10) is essential for oligodendrocyte precursor development and myelination in the mouse brain

“…Growing evidence has implicated neuroin ammationinduced demyelination as an important pathological features in major depressive disorder (MDD) and multiple sclerosis (MS), and myelin de cits contribute to mood swing and cognitive decline. 17,18,33 Our results using FluoroMyelin Green uorescent myelin staining, electron microscopy, immunohistochemistry, and western blotting demonstrated that deletion of ADAM10 in OPCs caused signi cant premyelination on P30 but demyelination on P60. In further studies, we found that conditional deletion of ADAM10 in OPCs interfered with the development of OPCs and decreased OPC proliferation in ADAM10 cKO mice.…”

The Eph receptor A4-mediated demyelination in depression

“…Using the chronic, unpredictable mild stress (CUMS) exposure or lipopolysaccharide (LPS) administrationinduced animal model of depression, the authors first analyzed the association between depression and demyelination. They conducted the three most commonly used behavioral tests for depression and found depressive-like behavior in the CUMS and LPS-induced depression models [1]. Moreover, the myelin basic protein (MBP) staining and the luxor fast blue (LFB) staining demonstrated a significantly decreased myelination in the depressive animal models, which was also confirmed by Western blotting.…”

“…Major depressive disorder (MDD), also known as clinical depression or depression, is one of the most common mental illnesses. It is characterized by pervasive and persistent low mood, disturbed memory, concentration, sleep, low motivation, and a loss of interest in enjoyable activities [1,2]. Evidence from genetic, neuroimaging, nonhuman animals and post-mortem has suggested abnormal myelination in the MDD [3].…”

“…The molecular mechanism underlying demyelination and synaptic deficits in depression is largely unknown. In a recent study, Li and his colleagues found that the ephrin A4 receptor (EphA4), a member of the Eph family of receptor tyrosine kinases, was essential to mediate demyelination and regulate synaptogenesis in depression [1]. The authors hypothesized that depression would include demyelination, and the increased EphA4 levels mediate demyelination and depression-like behaviors.…”

“…To elucidate the mechanism underlying the association between demyelination and depression, the authors per-formed RNA-seq using hippocampal tissue from CUMS mice. The expression of EphA4 was significantly upregulated in CUMS mice and selected for further analysis due to its essential role in regulating synapse development, synaptic plasticity, neuronal growth, and its increased levels in axonal lesions in the demyelinating brain disorder [1,5]. Intriguingly, the authors found that the ubiquitinmediated degradation pathway contributes to the changes in EphA4 levels.…”