Cumulative Activation of Akt and Consequent Inhibition of Glycogen Synthase Kinase-3 by Brain-Derived Neurotrophic Factor and Insulin-Like Growth Factor-1 in Cultured Hippocampal Neurons

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Abstract
Brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) seem to play key roles in mediating neuronal plasticity in the hippocampus. In the current studies, we have used cultured hippocampal neurons to study possible interactions between the two growth factors in modulating neuronal signaling pathways. BDNF and IGF-1 were found to each effectively activate the neuroprotective Akt pathway, with the magnitude of activation being at least additive when cultures were simultaneously treated with supramaximal concentrations of peptides. Likewise, a cumulative inhibitory Akt-dependent phosphorylation of proapoptotic glycogen synthase kinase-3 was observed. Immunofluorescent studies demonstrated that a single population of neurons responded to BDNF and IGF-1. In contrast, the magnitude of BDNF-stimulated extracellular signal-regulated kinase (ERK) activation was found to be much greater than that of IGF-1-stimulated ERK, such that the difference in magnitude stimulated by BDNF in the presence and absence of IGF-1 did not reach statistical significance. Consistent with the observed agonist-stimulated activation of Akt, BDNF and IGF-1 were both found to act as neurotrophins, enhancing neuronal survival under low-insulin culture conditions. Maximal survival was achieved when both growth factors were present. These findings provide insight into the significance of multiple growth factors stimulating activation of ERK and Akt in the central nervous system. In some cases, the magnitude of activation required to elicit biological responses may be achieved only with a combination of compounds.