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

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.

Chronic Antidepressants Induce Redistribution and Differential Activation of αCaM Kinase II between Presynaptic Compartments

“…It has been shown that synapsin I is required for stimulation of glutamate release by brain-derived neurotrophic factor (BDNF) (Jovanovic et al, 2000). BDNF expression is increased and indirect evidence showed that more BDNF is released after chronic antidepressant treatments (Saarelainen et al, 2003). Now, if antidepressants increase the synaptic concentration of BDNF one would expect an upregulation of glutamate release rather than a downregulation, as we observed.…”

Interaction between BDNF and Serotonin: Role in Mood Disorders

“…For example, mice engineered with a forebrain-specific knockout of BDNF do not show differences in depressive-like behaviors per se, but fail to respond to antidepressants (Monteggia et al, 2004). This effect is phenocopied in mice that are deficient in BDNF or TrkB signaling, further suggesting that BDNF signaling via TrkB is important for mediating a response to antidepressants (Saarelainen et al, 2003). A major unanswered question is to what degree the effects of antidepressants are mediated via BDNF signaling.…”

“…There is clearly a discrepancy between the time course of increase in 5-HT (min) and that of increase in BDNF gene expression (days), induced by antidepressants. Thus, the rapid effects of antidepressants on FST/TST are likely mediated by an acute increase in BDNF secretion and/or TrkB signaling (Saarelainen et al, 2003), rather than by an enhancement of BDNF/TrkB gene expression. Future experiments should determine the behavioral effects of chronic treatment with antidepressants in BDNF and TrkB mutant mice.…”

Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results

“…Variation in BDNF has been thought to play a role in the etiology of affective disorders and the mediation of antidepressant treatment response (51). Furthermore, expression of BDNF has been shown to be modified by antidepressant treatment (52). A functional nonsynonymous SNP causing an amino acid substitution of valine to methionine has been identified in codon 66 (val66met; rs6265) (53,54).…”