Activation of the TrkB neurotrophin receptor by antidepressant drugs

Hanna Antila

Research output: ThesisDoctoral ThesisCollection of Articles


Major depressive disorder is one of the most significant causes of disability worldwide. Currently, the main treatment options for depression are psychotherapy and antidepressant drugs that pharmacologically target the monoamine systems such as serotonin transporter (SERT) blocker fluoxetine. It has been hypothesized that impairments in synaptic function and plasticity, caused for example by stress, could underlie the manifestation of depression. Moreover, in rodent models chronic treatment with antidepressant drugs has been shown to enhance plasticity of the adult brain via brain-derived neurotrophic factor (BDNF). The effects of BDNF mediated via its receptor tropomyosin receptor kinase B (TrkB) promote synapse function and thus could facilitate recovery from depression. Interestingly, antidepressant drugs with different main pharmacological targets seem to share the ability to activate the TrkB receptor, however, the mechanisms how antidepressant drugs activate TrkB are not known. The delayed onset of action and limited therapeutic efficacy of antidepressant drugs has promoted interest toward finding more rapid-acting and effective treatment options for depression. Electroconvulsive therapy has been the treatment of choice for treatment resistant depressed patients, however, side effects and the disrepute among general public has limited its use. Recently, subanesthetic doses of dissociative anesthetic ketamine have been shown to rapidly alleviate depression symptoms in depressed patients who do not respond to conventional antidepressant drugs. The effects of ketamine on mood appear already couple of hours after single intravenous infusion and last for about one week. Ketamine has been shown to induce mammalian target of rapamycin (mTOR) via BDNF-TrkB signaling, rapidly promote synaptogenesis and alter neural network function. Furthermore, in small human studies another anesthetic isoflurane has rapidly alleviated symptoms of depressed patients. Yet, the potential of isoflurane in the treatment of depression has not been studied in large clinical trials. Since TrkB receptor is involved in regulation of synaptic plasticity, drugs that act as agonists or positive allosteric modulators of TrkB could be potentially beneficial in the treatment of CNS disorders characterized by impaired plasticity. The first aim of our studies was to develop a platform suitable for high-throughput screening of compounds regulating TrkB activity. We developed an in situ ELISA (enzyme-linked immunosorbent assay) method that detects phosphorylated TrkB receptors from cultured cells. The main advantage of the in situ ELISA compared to conventional ELISA is that the cells are cultivated directly on the ELISA plate making the additional transfer step of the cellular material from the cell culture plate to the ELISA plate unnecessary. To further validate the in situ ELISA method, we conducted a proof-of-concept screening of a small chemical library and found several compounds that dose-dependently activated TrkB receptor or inhibited BDNF-induced TrkB activation. The second aim was to examine the mechanism how the antidepressant drugs activate TrkB. Interestingly, we found that antidepressant drugs activate TrkB independently of BDNF. Moreover, SERT, the main pharmacological target of fluoxetine, was not required for the fluoxetine-induced TrkB activation. Furthermore, the antidepressant-induced TrkB activation was developmentally regulated. The ability of antidepressants to activate TrkB appeared around postnatal day 12. Interestingly, at this same developmental timepoint (P12) the ability of BDNF to activate TrkB decreased dramatically. Finally, we aimed to characterize the neurobiological basis for the possible antidepressant effects of isoflurane. We found that brief isoflurane anesthesia rapidly and transiently activated the TrkB-mTOR signaling and produced antidepressant-like behavioral response in the forced swim test in a TrkB-dependent manner. Single isoflurane treatment also produced an antidepressant-like phenotype in behavioral paradigms that normally require chronic treatment with conventional antidepressant drugs, suggesting that isoflurane may have rapid antidepressant effects similar to ketamine. Moreover, isoflurane facilitated hippocampal long-term potentiation when measured 24 hours after the treatment and affected the general neural network function by increasing activity of the parvalbumin-positive inhibitory interneurons in the hippocampus. In conclusion, our results improve the understanding of the mechanism of action of conventional antidepressant drugs and provide plausible neurobiological basis for the antidepressant effects of isoflurane. Our findings also support examining further the potential of anesthetics in the treatment of depressed patients who do not respond to the current treatment options.
Original languageEnglish
Place of PublicationHelsinki
Print ISBNs978-951-51-2424-1
Electronic ISBNs978-951-51-2425-8
Publication statusPublished - 2016
MoE publication typeG5 Doctoral dissertation (article)

Fields of Science

  • 3112 Neurosciences

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