The possible role of O‐GlcNAc modification in the pathogenesis of depression disorder

Diabetes mellitus leads to a number of complications involving brain function, including cognitive decline and depression. Depression is linked to impaired adult neurogenesis in the gyrus dentatus of the hippocampus, but the underlying molecular mechanisms are incompletely understood. The process of neurogenesis consists of the proliferation of neural progenitors and differentiation of new neurons, and the chloride conductance ICl swell , activated after anisosmotic cell swelling during cell volume regulation, is thought to be essential in cell proliferation and differentiation. Diabetes also leads to increase in the post‐translational O‐GlcNAcylation (O‐GlcNAc) of cellular proteins. Recently, the protein ICln, which is crucial in the activation of the current ICl swell , has been found to be O‐GlcNacylated. In the present study, we investigated the characteristic of the current ICl swell following O‐GlcNAc elevation in neuronal‐like SH‐SY5Y and HEK 293 Phoenix cells, with focus on the role of ICln. In parallel to cell viability tests, ICl swell was measured by patch‐clamp in native cells or cells overexpressing either the wild type or non‐glycosilable forms of ICln (IClnT223A, IClnS193X and IClnS67A). O‐GlcNAc elevation significantly reduced the metabolic activity of SH‐SY5Y and HEK 293 Phoenix cells. In SH‐SY5Y cells, O‐GlcNAc elevation significantly suppressed the basally activated ICl swell current. In HEK 293 Phoenix cells, O‐GlcNAc elevation inhibited the ICln‐induced ICl swell current, with no effect on the endogenous ICl swell current, thus indicating that O‐GlcNAc impairs the ICln function. The IClnT223A‐induced current was similar to IClnWT‐induced current and was similarly suppressed after O‐GlcNAc elevation. IClnS193X lost most of its activity, though the residual current was sensitive to O‐GlcNAc elevation. Finally, the IClnS67A‐induced current is similar to the IClnWT‐induced current, but insensitive to O‐GlcNAc elevation. The present work underscores the essential role of O‐GlcNAcylation in governing the ICl swell current through modification of the ICln protein. The results indicate that the O‐GlcNAc modification site responsible for the suppression of the ICln‐induced current should be located upstream the amino acid 193, most likely on Serine 67. We conclude that O‐GlcNAcylation of the ICl swell activator ICln in the context of hyperglycaemic conditions may lead to ICl swell inhibition in brain, which may result in reduced adult neurogenesis and eventually in the depression disorder. We suggest that the protein ICln may represent a novel target in the prevention or treatment of pathological states characterized by chronically elevated O‐GlcNAcylation of cellular proteins, including mood disorders linked to hyperglycaemia