Activation of the TrkB Neurotrophin Receptor Is Induced by Antidepressant Drugs and Is Required for Antidepressant-Induced Behavioral Effects

TLDR

Neurotrophin signaling, enhanced by antidepressants, can produce antidepressant‑like behavior and may promote synaptic connectivity that underlies clinical mood recovery. The study investigates whether endogenous BDNF and its receptor trkB mediate the behavioral effects of antidepressant drugs. Using transgenic mice with altered trkB or BDNF expression, the authors assessed forced swim test responses and measured trkB phosphorylation in cortical regions after acute and chronic antidepressant treatment. Mice with reduced trkB activation or BDNF deficiency were resistant to antidepressants, whereas neurotrophin‑3 heterozygotes responded normally, and antidepressant treatment acutely increased trkB autophosphorylation and CREB phosphorylation in prefrontal, anterior cingulate, and hippocampal cortex.

Abstract

Recent studies have indicated that exogenously administered neurotrophins produce antidepressant-like behavioral effects. We have here investigated the role of endogenous brain-derived neurotrophic factor (BDNF) and its receptor trkB in the mechanism of action of antidepressant drugs. We found that trkB.T1-overexpressing transgenic mice, which show reduced trkB activation in brain, as well as heterozygous BDNF null (BDNF(+/)-) mice, were resistant to the effects of antidepressants in the forced swim test, indicating that normal trkB signaling is required for the behavioral effects typically produced by antidepressants. In contrast, neurotrophin-3(+/)- mice showed a normal behavioral response to antidepressants. Furthermore, acute as well as chronic antidepressant treatment induced autophosphorylation and activation of trkB in cerebral cortex, particularly in the prefrontal and anterior cingulate cortex and hippocampus. Tyrosines in the trkB autophosphorylation site were phosphorylated in response to antidepressants, but phosphorylation of the shc binding site was not observed. Nevertheless, phosphorylation of cAMP response element-binding protein was increased by antidepressants in the prefrontal cortex concomitantly with trkB phosphorylation and this response was reduced in trkB.T1-overexpressing mice. Our data suggest that antidepressants acutely increase trkB signaling in a BDNF-dependent manner in cerebral cortex and that this signaling is required for the behavioral effects typical of antidepressant drugs. Neurotrophin signaling increased by antidepressants may induce formation and stabilization of synaptic connectivity, which gradually leads to the clinical antidepressive effects and mood recovery.