Antidepressant Drugs Transactivate TrkB Neurotrophin Receptors in the Adult Rodent Brain Independently of BDNF and Monoamine Transporter Blockade

June 22, 2012

Background: 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. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands. Methodology: In 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 Findings: Using 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 (132.48.5% 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. Conclusions: The 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.

  • Ethan Perlstein

    When pressed, most psychopharmacologists will admit that the serotonin hypothesis of depression and antidepressant (AD) function is an oversimplification, though a few holdouts look askance at any model not rooted solely in neurotransmitter levels. The rival theory, if you can even call it that, is generally referred to as the neurotrophic hypothesis. It was originally developed to explain the observations of antidepressant-induced cellular growth in specific brain regions, e.g., the hippocampus, made by Eric Nestler and Ron Duman in the mid 90s. The reason why the serotonin hypothesis falls short is that brain cell growth, or neurotrophism, only occurs after chronic (14 days) but not acute (30 minutes) antidepressant treatment.

    That’s what makes this PLoS ONE paper from Eero Castren’s group so interesting, because they found an acute AD effect on the classic neurotrophic signaling pathway. For some context, the AD-induced neurotrophic effect requires a protein called BDNF (brain-derived neurotrophic factor), which binds to a receptor called Trk (tropomyosin-related kinase), of which there are two subunits, TrkA and TrkB. In the paper, the authors measured the phosphorylation status, i.e., activation level, of TrkB using phospho-specific antibodies in response to ADs in vivo and in vitro.

    But that’s not all. They used a transgenic knock-in mouse whose TrkB was mutated by one amino acid, rendering its TrkB receptors sensitive to the inactivating effects of a secondary compound that could be co-administered with ADs in experiments. That way they could explicitly test the requirement for TrkB in any AD-induced effects. Surprisingly, a 30-minute AD exposure caused TrkB to be phosphorylated in two regions of the brains of drugged mice, including the hippocampus. They also found that an immature form of phosphorylated TrkB, presumably in the Golgi, accumulated during the AD treatment. I would like to see more controls done to confirm TrkB compartmentalization/localization, but their evidence is fairly convincing in present form.

    For the rest of paper the authors performed a score of specificity controls, accounting for known AD polypharmacology. They showed that the endogenous ligand for TrkB, namely BDNF, is not required for the effect; nor are the serotonin or norepinephrine reuptake transporters, SERT and NET, respectively; nor are adenosine receptors. Curiously, the effect was not observed in primary neuronal cultures or cell lines transfected with TrkB and treated with ADs. Therefore, the effect was observed only in live animals treated with ADs.

    My interpretation is that TrkB receptors are activated via membrane effects, in much that same way that mechanosensitive ion channel function is affected by charged amphipaths that accumulate in lipid bilayer; or the way that anesthetics alter excitatory ion channel function via lateral pressure changes caused by membrane partitioning. I’m not sure how to explain the in vivo vs in vitro difference, other than that membrane accumulation is somehow affected by cellular milieu, as the authors argued. But I would look specifically at membranes as a focus of study to begin to understand why the cell culture environment is non-permissive.

    I highly recommend this paper. (Click through to using the Mendeley link on the side panel). It’s short and sweet as neuropharmacology papers go. And more importantly, it’s fully Open Access! Enjoy.