Differential effects of transient and sustained activation of BDNF‐TrkB signaling

Abstract

Brain-derived neurotrophic factor (BDNF) serves a pleiotropic role in the central nervous system, ranging from promoting neuronal survival and differentiation during development and synaptic modulation in the adult. An important, yet unanswered question is how BDNF could serve such diverse functions, sometimes in the same cell. At least two modes of BDNF actions have been elucidated so far based on BDNF signaling kinetics and/or the activity status of the responding neurons. Acute and gradual increases in extracellular BDNF concentrations elicit, respectively, transient and sustained activation of TrkB receptor and its downstream signaling, leading to differential molecular and cellular functions. In cultured neurons, sustained TrkB activation promotes neuronal dendritic arborization and spinogenesis, whereas transient TrkB activation facilitates dendritic growth and spine morphogenesis. In hippocampal slices, slow delivery of BDNF facilitates LTP, whereas fast application of BDNF enhances basal synaptic transmission in schaffer collateral synapses. High-frequency stimulation of neurons converts BDNF-induced TrkB signaling from a transient to a sustained mode. These initial insights lay the foundation for future investigation of the BDNF-TrkB pathway, and analogous signaling pathways to gain a comprehensive understanding to enable translational research. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 647-659, 2018.

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“…8,17 These molecular agents, then, seemingly involved with downstream signal transmission, speak in support of a neurotrophic hypothesis of depression, which suggests that affective dysregulation may be the result of neurogenesis and synaptic plasticity-related pathology. 9,17 Further research could reveal a better understanding of eEF2 kinase and its role in BDNF mediation, and additional analysis is needed to identify potential intercellular and intracellular process aberrations which may account for distinct manic and depressive episodes. 9,17 A rethinking of affective illness and its treatment is clearly underway.…”

“…17 BDNF is a protein which acts as a neurotrophic growth factor and supports neuronal cell health. 17 BDNF protein synthesis is in part modulated by eukaryotic elongation factor 2 kinase (eEF2 kinase), which phosphorylates eukaryotic elongation factor 2 (eEF2), a principal modulator of protein synthesis and synaptic plasticity. 9 The phosphorylation of eEF2 renders it inactive, which decreases BDNF protein synthesis.…”

“…Brain‐derived neurotrophic factor (BDNF) studies have also contributed to these downstream signal transduction cascade theories . BDNF is a protein which acts as a neurotrophic growth factor and supports neuronal cell health .…”

“…A current hypothetical model of the rapid antidepressant effect precipitated by NMDA‐receptor blockade suggests that in blocking the NMDA receptors associated with the constitutive activity of glutamate receptors, eEF2 kinase is inhibited, the phosphorylation of eEF2 does not occur, and BDNF protein production increases . It is theorized that this cascade ultimately results in long‐term potentiation and an antidepressant effect …”

“…Future research could investigate potential methods of manipulating constitutional NMDA‐receptor activity to precipitate a rapid antidepressant effect . Another area of interesting work is clearly that involving BDNF and its role in maintaining neuron cell functioning …”