Beta N ‐acetylglucosaminyltransferase V (Mgat5) deficiency reduces the depression‐like phenotype in mice

The central nervous system (CNS) is rich in glycoconjugates, located on cell surface and in extracellular matrix. The products of Golgi UDP‐GlcNAc: N ‐acetylglucosaminyltransferases (encoded by Mgat1, Mgat2, Mgat4 and Mgat5) act sequentially to generate the GlcNAc‐branched complex‐type N ‐glycans on glycoprotein receptors. While elimination of all the branched N ‐glycans in Mgat1 −/− mouse embryos is lethal at neural tube fold stage, decreased branching is associated with late developmental defects similar to type 2 of congenital disorders of glycosylation, with developmental and psychomotor abnormalities. To study the role of complex‐type N ‐glycans in brain function, we tested Mgat5 −/− mice in a battery of neurological and behavioral tests. Despite the absence of tri‐ and tetra‐antennary products, Mgat5 −/− mice were not different from their wild‐type littermates in physical and neurological assessments, anxiety level, startle reactivity and sensorimotor gating. However, they displayed a robust decrease in the immobility time in the forced swim test and the tail suspension test independent of locomotor activity, interpreted as a change in depression‐like behavior. This effect was accentuated after chronic mild stress. Comparable increase in plasma corticosterone of Mgat5 +/+ and Mgat5 −/− mice in response to acute stress shows an intact function of the hypothalamus–pituitary–adrenal axis. A change in social interactions was also observed. Our results indicate that Mgat5 modification of complex‐type N ‐glycans on CNS glycoproteins is involved in the regulation of depression‐like behavior.