The Role of Neurotrophins in Major Depressive Disorder

Abstract

Neurotrophins and other growth factors have been advanced as critical modulators of depressive behavior. Support for this model is based on analyses of knockout and transgenic mouse models, human genetic studies, and screens for gene products that are regulated by depressive behavior and/or antidepressants. Even subtle alteration in the regulated secretion of brain-derived neurotrophic factor (BDNF), for example, due to a single nucleotide polymorphism (SNP)-encoded Val-Met substitution in proBDNF that affects processing and sorting, impacts behavior and cognition. Alterations in growth factor expression result in changes in neurogenesis as well as structural changes in neuronal cytoarchitecture, including effects on dendritic length and spine density, in the hippocampus, nucleus accumbens, and prefrontal cortex. These changes have the potential to impact the plasticity and stability of synapses in the CNS, and the complex brain circuitry that regulates behavior. Here we review the role that neurotrophins play in the modulation of depressive behavior, and the downstream signaling targets they regulate that potentially mediate these behavioral pro-depressant and antidepressant effects.

Keywords: Antidepressant; Arc; Brain-Derived Neurotrophic Factor (BDNF); Depression; Ketamine; Nerve Growth Factor (NGF); Neuritin; Neurtrophin-3 (NT-3); Trk; VGF.

Figures

Figure 1

Hippocampal BDNF/TrkB signaling pathways that modulate depressive behavior and antidepressant responses. Binding of BDNF to TrkB activates different intracellular signaling cascades, including the PI3K/Akt, Ras/ERK (MAPK) and PLCγ pathways [12]. Phosphorylation of Y490 of TrkB leads to recruitment of adaptor proteins such as Shc, Grb2 and Gab1 and subsequent activation of the PI3K/Akt pathway [192] and Rho family of GTPases (RhoA, Rac, Cdc42), which positively regulate actin polymerization through downstream signaling including ROCK/PAK, LimK and Cofilin [151-153]. Another downstream effector of the PI3K/Akt pathway is GSK-3, whose activity is negatively regulated by Akt-mediated phosphorylation [193]. One of the downstream targets of GSK-3 is β-catenin, which can be translocated into the nucleus to promote gene expression. The mTOR pathway, which facilitates local translation and the rapid antidepressant effects of ketamine, is also regulated by PI3K/Akt signaling [122]. Activation of PI3K/Akt signaling is believed to positively modulate spinogenesis, synaptogenesis and neurogenesis, thus inducing antidepressant effects. In addition to inductive effects on gene expression, the Ras/ERK (MAPK) pathway also acts through Rho family of GTPases, mTOR signaling, and synapsin to induce spinogenesis, synaptogenesis and neurogenesis (not shown) [122, 153, 154]. Phosphorylation of Y816 of TrkB recruits PLCγ [194], inducing the hydrolysis of PIP2 to IP3 and DAG. IP3 regulates calcium release and CAMK activation, while DAG activates PKC. Both IP3/CAMK and DAG/PKC signaling regulate synaptic plasticity [195], however their roles in depression remain largely unknown.