Inhibition of MNKs by CGP57380 or MNK-I1 blocks the BDNF-induced increases in phospho-eIF4E and global protein synthesis. A, Representative Western blots for the indicated proteins or phosphoproteins. B, C, The effect of treating neurons with CGP57380 before BDNF stimulation on eIF4E and ERK phoshporylation. two-way (BDNF × CGP57380) ANOVAs revealed main effects of BDNF on phospho-eIF4E (F(1,28) = 4.9, p = 0.03) and phospho-ERK (F(1,20) = 205, p < 0.001), a main effect of CGP57380 on phospho-eIF4E (F(1,28) = 142, p < 0.001) but not phospho-ERK (p = 0.78), and an interaction between BDNF and CGP57380 administration on phospho-eIF4E (F(1,28) = 9.6, p = 0.004) but not phospho-ERK (p = 0.94); n = 6–8. D, Neurons were treated with CGP57380 before BDNF stimulation in the presence of [35S]methionine. A two-way (BDNF × CGP57380) ANOVA revealed a main effect of BDNF (F(1,45) = 4.1, p = 0.05), a main effect of CGP57380 (F(1,45) = 18.9, p < 0.001), and an interaction between BDNF and CGP57380 administration (F(1,45) = 4.7, p = 0.04); n = 11–12. E, Representative Western blots for parts (F) and (G). F, G, The effect of treating neurons with MNK-I1 before BDNF stimulation on eIF4E and ERK phosphorylation. Two-way (BDNF × MNK-I1) ANOVAs revealed main effects of BDNF on phospho-eIF4E (F(1,16) = 12.7, p = 0.003) and phospho-ERK (F(1,24) = 194, p < 0.001), a main effect of MNK-I1 on phospho-eIF4E (F(1,16) = 55.8, p < 0.001) but not phospho-ERK (p = 0.36), and an interaction between BDNF and MNK-I1 administration on phospho-eIF4E (F(1,16) = 9.8, p = 0.006) but not phospho-ERK (p = 0.37); n = 5. H, Neurons were treated with MNK-I1 before BDNF stimulation in the presence of [35S]methionine. A two-way (BDNF × MNK-I1) ANOVA revealed a main effect of BDNF (F(1,56) = 8.8, p = 0.005), a main effect of MNK-I1 (F(1,56) = 42.0, p < 0.001), and an interaction between BDNF and MNK-I1 administration (F(1,56) = 5.0, p = 0.028); n = 12; *p < 0.05 compared with NT. Error bars represent SEM.