Rislenemdaz Treatment In The Lateral Habenula Improves Despair-like Behavior In Mice

The specific Glu N2 B antagonist rislenemdaz(Ris;a.k.a.MK-0657 and CERC-301)is in phase II clinical trial as an anti-depressive drug,but the working mechanism for its antidepressant effects is not clearly understood.Given the important role of the lateral habenula(LHb)in the pathogenesis of depression and the fact that Glu N2B-containing N-methyl-D-aspartate receptors and brain-derived neurotrophic factor(BDNF)are expressed in the LHb,we conducted a study to examine whether the LHb mediates Ris' antidepressant effects in a chronic restraint stress(CRS)-induced depressive-like mouse model.In this study,Ris was administered systemically or locally into the LHb.Short hairpin RNAs were used to knock down BDNF in the LHb.Depressive-like behaviors were assessed with the open field test,forced swimming test,tail suspension test,and sucrose preference test.Expression of Glu N2 B,BDNF,and c-Fos in the LHb were analyzed with western blotting and immunohistochemistry under condition with Ris administered systemically or with BDNF knockdown in the LHb.We found that both systemic and intra-LHb administration of Ris alleviated CRS-induced despair-like behavior and that systemic Ris reduced LHb expression of Glu N2 B,BDNF,and c-Fos(a neuronal activity marker).Specific knockdown of BDNF in the LHb prevented CRS-induced despair-like behavior,while preventing CRS-induced increases in BDNF and c-Fos expression in the LHb.Together these results suggest that Ris may exert its antidepressant effects through affecting the LHb such as downregulating BDNF expression in the LHb.