Exogenous L-fucose attenuates depression induced by chronic unpredictable stress: Implicating core fucosylation has an antidepressant potential

Core fucosylation is one of the most essential modifications of the N -glycans, catalyzed by α1,6-fucosyltransferase (Fut8), which transfers fucose from guanosine 5′-diphosphate (GDP)-fucose to the innermost N -acetylglucosamine residue of N -glycans in an α1-6 linkage. Our previous studies demonstrated that lipopolysaccharide (LPS) can induce a more robust neuroinflammatory response in Fut8 homozygous knockout (KO) ( Fut8 −/− ) and heterozygous KO ( Fut8 +/− ) mice contrasted to the wild-type ( Fut8 +/+ ) mice. Exogenous administration of L-fucose suppressed LPS-induced neuroinflammation. Numerous studies indicate that neuroinflammation plays a vital role in the development of depression. Here, we investigated whether core fucosylation regulates depression induced by chronic unpredictable stress (CUS), a well-established model for depression. Our results showed that Fut8 +/− mice exhibited depressive-like behaviors and increased neuroinflammation earlier than Fut8 +/+ mice. Administration of L-fucose significantly reduced CUS-induced depressive-like behaviors and pro-inflammatory cytokine levels in Fut8 +/− mice. The L-fucose treatment produced antidepressant effects by attenuating the complex formation between gp130 and the interleukin-6 (IL-6) receptor and the JAK2/STAT3 signaling pathway. Notably, L-fucose treatment increased dendritic spine density and postsynaptic density protein 95 (PSD-95) expression, which were suppressed in CUS-induced depression. Furthermore, the effects of L-fucose on the CUS-induced depression were also observed in Fut8 +/+ mice. Our results clearly demonstrate that L-fucose ameliorates neuroinflammation and synaptic defects in CUS-induced depression, implicating that core fucosylation has significant anti-neuroinflammatory activity and an antidepressant potential.