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 di!erentiation of new neurons, and the chloride conductance ICl , activated after anisosmotic cell swelling during cell volume regulation, is thought to be essential in cell proliferation and di!erentiation. 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 , has been found to be O‐GlcNacylated. In the present study, we investigated the characteristic of the current ICl 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 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). OGlcNAc elevation signi"cantly reduced the metabolic activity of SH‐SY5Y and HEK 293 Phoenix cells. In SHSY5Y cells, O‐GlcNAc elevation signi"cantly suppressed the basally activated ICl current. In HEK 293 Phoenix cells, O‐GlcNAc elevation inhibited the IClninduced ICl current, with no e!ect on the endogenous ICl current, thus indicating that OGlcNAc impairs the ICln function. The IClnT223Ainduced 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 IClnWTinduced current, but insensitive to O‐GlcNAc elevation. The present work underscores the essential role of OGlcNAcylation in governing the ICl current through modi"cation of the ICln protein. The results indicate that the O‐GlcNAc modi"cation 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 activator ICln in the context of hyperglycaemic conditions may lead to ICl 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