Abstract
BackgroundAntidepressant drugs (ADs) have been shown to activate BDNF (brain-derived neurotrophic factor) receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands.MethodologyIn this study we examined the role of BDNF, TrkB kinase activity and monoamine reuptake in the AD-induced TrkB activation in vivo and in vitro by employing several transgenic mouse models, cultured neurons and TrkB-expressing cell lines.Principal FindingsUsing a chemical-genetic TrkBF616A mutant and TrkB overexpressing mice, we demonstrate that ADs specifically activate both the maturely and immaturely glycosylated forms of TrkB receptors in the brain in a TrkB kinase dependent manner. However, the tricyclic AD imipramine readily induced the phosphorylation of TrkB receptors in conditional bdnf −/− knock-out mice (132.4±8.5% of control; P = 0.01), indicating that BDNF is not required for the TrkB activation. Moreover, using serotonin transporter (SERT) deficient mice and chemical lesions of monoaminergic neurons we show that neither a functional SERT nor monoamines are required for the TrkB phosphorylation response induced by the serotonin selective reuptake inhibitors fluoxetine or citalopram, or norepinephrine selective reuptake inhibitor reboxetine. However, neither ADs nor monoamine transmitters activated TrkB in cultured neurons or cell lines expressing TrkB receptors, arguing that ADs do not directly bind to TrkB.ConclusionsThe present findings suggest that ADs transactivate brain TrkB receptors independently of BDNF and monoamine reuptake blockade and emphasize the need of an intact tissue context for the ability of ADs to induce TrkB activity in brain.
Highlights
TrkB neurotrophin receptor transduces intracellular signaling events that are critical for neuronal differentiation, survival and plasticity throughout life [1,2,3,4,5]
The present findings suggest that Antidepressant drugs (ADs) transactivate brain TrkB receptors independently of Brainderived neurotrophic factor (BDNF) and monoamine reuptake blockade and emphasize the need of an intact tissue context for the ability of ADs to induce TrkB activity in brain
We show that both mature and immature forms of TrkB can be tyrosine phosphorylated by ADs, but neither the endogenous ligand BDNF, nor the serotonin transporter (SERT), the principal target of many ADs, is required for this effect
Summary
TrkB (tropomyosin-related kinase B) neurotrophin receptor transduces intracellular signaling events that are critical for neuronal differentiation, survival and plasticity throughout life [1,2,3,4,5]. Brainderived neurotrophic factor (BDNF) is the main endogenous ligand for TrkB [3], but recent evidence demonstrates that TrkB can be transactivated independently of BDNF or other neurotrophins through neuromodulator receptors [6,7] and small molecules [8,9]. Accumulating evidence suggests that antidepressant drugs (AD) that regulate the brain levels of monoamine neurotransmitters serotonin and norepinephrine, act at least partially by activating TrkB receptor signaling in brain [13,14]. Antidepressant drugs (ADs) have been shown to activate BDNF (brain-derived neurotrophic factor) receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. Recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands
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