Abstract
Repeated stressful events are associated with the onset of major depressive disorder (MDD). We previously showed oligodendrocyte (OL)-specific activation of the serum/glucocorticoid-regulated kinase (SGK)1 cascade, increased expression of axon-myelin adhesion molecules, and elaboration of the oligodendrocytic arbor in the corpus callosum of chronically stressed mice. In the current study, we demonstrate that the nodes and paranodes of Ranvier in the corpus callosum were narrower in these mice. Chronic stress also led to diffuse redistribution of Caspr and Kv 1.1 and decreased the activity in white matter, suggesting a link between morphological changes in OLs and inhibition of axonal activity. OL primary cultures subjected to chronic stress resulted in SGK1 activation and translocation to the nucleus, where it inhibited the transcription of metabotropic glutamate receptors (mGluRs). Furthermore, the cAMP level and membrane potential of OLs were reduced by chronic stress exposure. We showed by diffusion tensor imaging that the corpus callosum of patients with MDD exhibited reduced fractional anisotropy, reflecting compromised white matter integrity possibly caused by axonal damage. Our findings suggest that chronic stress disrupts the organization of the nodes of Ranvier by suppressing mGluR activation in OLs, and that specific white matter abnormalities are closely associated with MDD onset.
Highlights
Repeated stressful events are associated with the onset of major depressive disorder (MDD)
We previously reported that in the corpus callosum of mice exposed to chronic stress, oligodendrocytic processes are thicker, more numerous, and longer[5,6,7]
We did not find any additional lesions such as hypo- or demyelination in the corpus callosum of either group (Fig. 1A–D). These results indicated that decreases of nodal and paranodal lengths in the corpus callosum might be induced by chronic stress exposure
Summary
Repeated stressful events are associated with the onset of major depressive disorder (MDD). We previously reported that chronically stressed mice with elevated plasma levels of corticosterone exhibit increased serum/glucocorticoid-inducible kinase (SGK)[1] phosphorylation in OLs located in nerve fiber bundles www.nature.com/scientificreports/ Such as the corpus callosum[5,6,7]. In order to clarify the relationship between excessive arborization of oligodendrocytic processes in rodent models of MDD and the molecular pathogenesis of this disorder in humans, in this study, we investigated the mechanisms underlying myelin-axon interactions at nodes and paranodes of the corpus callosum To this end, we analyzed the expression of several adhesion molecules and channels identified in the nodes of Ranvier in mice by immunohistochemistry[10,11,12].
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