Fig. 4: Inhibition of ERK signaling significantly abolishes the antidepressant-like actions and upregulation of VGF, BDNF, and ERK/mTOR signaling produced by repeated treatment with rapastinel in mice.

A Schematic demonstrating the timeline for cannula implanted, CUS exposure, drug treatment, and behavioral tasks. B, C Pretreatment with PD98059 significantly alleviated effects of rapastinel on CUS-induced decrease of locomotor activity in the OFT, as assessed by line crossings (B) and rearings (C). D Inhibition of ERK signaling blocks the rapastinel treatment rapidly reversed anhedonia as measured by a reduction in 1% sucrose preference after CUS. E Rapastinel administration rapidly reversed the changes in latency to feed in the NSFT. F Rapastinel significantly prevented CUS-induced increase in immobility time in FST. G and L Representative western blot images; H and M Quantitative analysis of blots (p-ERK, ERK, p-mTOR, p-p70S6K, and p-4E-BP1). C Immunofluorescent images of BDNF and VGF in the CA1, CA2/3, and DG regions in the hippocampus (I) and PFC (N) of mice. Rapastinel reversed the CUS-induced downregulation of expression of BDNF (green) with VGF (red) in hippocampus (J and K) and PFC (O) neurons in mice. PD98059 can abolish the antidepressant effect of rapastinel in the expression of BDNF (green) and VGF (red) in hippocampus and PFC neurons in mice. Scale bar = 200 μm. Data are expressed as means ± S.E.M; n = 9 for behavioral tasks, n = 3/mice for western blot and n = 5/mice for immunofluorescence; **P < 0.01 compared with the vehicle + non-stressed group; ##P < 0.01 compared with the vehicle + CUS group; @P < 0.05, @@P < 0.01 compared with the rapastinel + CUS group.