Prof. Eero Castrén

Team Name: ‘Trophins’

Link to team page: http://www.helsinki.fi/neurosci/groups/castren.html

Institute: University of Helsinki

Address: P.O. Box 56, 00014 Helsinki, Finland

Description of research

Castrén lab is investigating the role of neurotrophic factors and their receptors on neuronal plasticity and drug responses in adult brain.  We have found that antidepressant drugs activate neurotrophin signaling and reactivate a developmental-like plasticity in the adult brain in rodents. We first found that fluoxetine, a widely prescribed antidepressant drug, induces critical period-like plasticity in the adult rat visual cortex and brings about a recovery of vision in an amblyopic eye, when drug treatment is combined with patching of the healthy eye.  We subsequently showed that fluoxetine treatment induces juvenile-like plasticity also in the amygdala, which may explain the enhanced effect of combined antidepressant drug treatment and psychotherapy in the treatment of traumatic memories.  Thus, drugs have no functional effects of their own, but by inducing plasticity they promote the effects of rehabilitation and psychotherapy. We have shown that signaling of the neurotrophin BDNF (brain-derived neurotrophic factor) and its receptor TrkB is required and sufficient for induction of plasticity and that several other drug classes also activate TrkB signaling. We are now focusing on the neuronal and molecular mechanisms underlying this phenomenon and investigating how adult plasticity could promote recovery in a variety of neuronal disorders. In addition to the JPND grant, the lab is supported by the European Research Council Advanced investigator award and grants from Sigrid Jusélius Foundation and Academy of Finland.

Research to be done in the context of Circprot

Activation of TrkB neurotrophin receptors is important for shaping dendritic spines. We expect that perturbation of TrkB signaling in NDs underlies deficiencies in LTP consolidation and spine plasticity. We will screen for proteins interacting with TrkB receptors in spines in response to TrkB activation. We have recently uncovered a unique set of interactors representing molecules involved in postsynaptic density organization, vesicular transport, and regulation of protein translation. Candidate TrkB interaction partners will now be verified using co-immunoprecipitation assays and the functional annotation of the interactors will be searched for through in vitro and in vivo methods. These interactions will be further studied in the Alzheimer’s and Huntington’s disease mouse model. The dependence of these interactions on TrkB phosphorylation will be studied using two complementary methods: First, we will use pharmacological treatment with fluoxetine and with fingolimod that increase TrkB signaling and BDNF synthesis, respectively. Second, we will use genetic means of promoting TrkB signaling by neuronal overexpression of TrkB in transgenic mice. We will further use lentivirally expressed OptoTrkB constructs where TrkB can be locally activated by blue light. TrkB activity will be inhibited using a chemical-genetic model by a specific inhibitor in TrkBF616A knockin mice or neuron-type specifically using conditional TrkB null mice (all these models are already available in our lab). TrkB phosphorylation will be induced or inhibited in AD and HD mouse models following acute (1 h) or chronic (21 days) stimulation with fluoxetine or fingolimod.
 The disease-dependent alterations in synaptic plasticity will be correlated with specific changes in Arc interactomes. These studies will take advantage of the identification of interacting proteins to understand how TrkB downstream signals possibly underlying specific defects in AD and HD.

Key publications

Saarelainen T., Hendolin P., Koponen E., Lucas G., MacDonald E., Agerman K., Haapasalo A., Nawa H., Ernfors P., Aloyz R. and Castrén E. Activation of the trkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J. Neurosci. 23 :349-357, 2003.

Maya Vetencourt JF, Sale A, Viegi A, Baroncelli L., De Pasquale R, O’Leary OF, Castrén E. and Maffei L. The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science, 320, 385-388, 2008.

Rantamäki T., Vesa L., Antila H., Di Lieto A., Tammela P., Schmitt A., Lesch K.-P., Rios M. and Castrén E. Antidepressant drugs transactivate TrkB neurotrophin receptors in the adult rodent brain independently of BDNF and monoamine transporter blockade. PLoS One 6 (6): e20567, 2011.

Karpova N.N., Pickenhagen A., Lindholm J., Tiraboschi E., Kulesskaya N., Ágústsdóttir A., Antila H., Popova D., Akamine Y., Sullivan R., Hen R., Drew L.J. and Castrén E. Fear erasure in mouse requres synergy between antidepressant drug treatment and exposure therapy. Science 334:1731-1734, 2011. (Evaluated by Faculty of 1000, rated as Exceptional)

Kemppainen S., Rantamäki T., Jerónimo-Santos A., Lavasseur G., Autio H., Karpova N., Kärkkäinen E., Stavén S., Miranda H.V., Outeiro T.F., Diógenes, M.J., Laroche S., Davis S., Sebastião A.M., Castrén E., Tanila H. Impaired TrkB receptor signaling contributes to memory impairment in APP/PS1 mice. Neurobiology of Aging, 33:1122.e23-39, 2012.