Eero Castrén Sigrid Jusélius Professor in Neuroscience, Research Director P.O. Box 56, FIN-00014 University of Helsinki Phone: +358-9-191 57626 Fax: +358-9-191 57620 E-mail: eero-dot-castren-at-helsinki-dot-fi

Sigrid Jusélius Laboratory
Physiological, Pathophysiological, and Pharmacological Roles of Neurotrophins in the Adult Brain    

Our interest is in the physiological and pathophysiological roles of neuronal plasticity and neurotrophins in the adult brain. We have developed mouse models of increased and decreased signaling of the trkB neurotrophin receptor in neurons. Using these mice and other experimental systems, we have shown a critical role of neurotrophin BDNF (brain-derived neurotrophic factor) in learning, memory, and emotionality. We have also demonstrated that neurotrophin signaling plays a critical role in the mechanism of action of several drugs, including antidepressants, opioid analgesics, and neuroprotective agents. We have used cultured neurons, organotypic cultures, and DNA microarrays to uncover the effects and mechanisms of neurotrophins and neuropsychiatric drugs in the brain. Future aims are to exploit our models to elucidate the roles of neurotrophins and the epigenetic regulation of the BDNF gene in the normal brain as well as in neurodevelopmental and neuropsychiatric disorders, to understand the roles and consequences of neurotrophin-mediated plastic responses in drug action, and to develop new models to search for drugs that will influence the effects of endogenous neurotrophins in the brain.

Personnel
Group leader: Sigrid Jusélius Professor in Neuroscience, Research Director Eero Castrén, MD, PhD
Post-doctoral fellows: Heidi Anthoni, PhD; Antonio Di Lieto, MD, PhD; Nina Karpova, PhD; Tomi Rantamäki, PhD (pharm); Ettore Tiraboschi, PhD; Xuefei Wu, PhD
Graduate students: Henri Autio, MSc (pharm);  Marie-Estelle Hokkanen, MSc; Juha Knuuttila, MSc; Jesse Lindholm, MSc (pharm)
Undergraduate students: Juha Simola; Liisa Vesa
Technician: Outi Nikkilä

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

Lucas, G., Hendolin, P., Harkany, T., Agerman, K., Paratcha, G., Holmgren, C., Zilberter, Y., Sairanen, M., Minichiello, L., Castrén, E., and Ernfors, P. (2003).  A reinforcement of morphine-induced analgesia by neurotrophin-4 mediated trkB activation. Nature Neuroscience 6: 221-222.

Koponen, E., Võikar, V., Riekki, R. , Saarelainen, T., Rauramaa, T., Rauvala, H., Taira, T., and Castrén, E. (2004). Transgenic mice overexpressing the full-length neurotrophin receptor trkB exhibit increased activation of trkB/PLCγ pathway, reduced anxiety, and facilitated learning. Mol. Cell. Neurosci. 26: 166-181.

Sairanen, M., Lucas, G., Ernfors, P., Castrén, M., and Castrén, E. (2005). BDNF and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation and survival in the adult dentate gyrus. J. Neurosci. 25: 1089-1094.

Castrén, E. (2005). Is mood chemistry? Nature Rev. Neurosci. 6: 241-246.

Castrén, M., Tervonen, T., Kärkkäinen, V., Heinonen, S., Castrén, E., Larsson, K., Bakker, C.E., Oostra, B.A., and Åkerman, K.E.O. (2005). Altered Differentiation of Neural Stem Cells in Fragile X Syndrome.  Proc. Natl. Acad. Sci. USA 102: 17834-17839.

De Wit, J., Eggers, R., Evers, R., Castrén, E., and Verhaagen, J. (2006). Long-term adeno-associated viral vector-mediated expression of truncated TrkB in the adult rat facial nucleus results in motor neuron degeneration.  J. Neurosci. 26: 1516-1530.

Tervonen, T., de Wit, J., Ajamian, F., Verhaagen, J., Castrén, E., and Castrén, M. (2006). Overexpression of truncated TrkB.T1 receptor induces proliferation of neural stem cells.  Eur. J. Neurosci. 24: 1277-1285.

Castrén, E., and Tanila, H.  (2006). Neurotrophins and dementia – keeping in touch. Neuron 51: 1-3.

Castrén, E., Võikar, V., and Rantamäki, T. (2007). Role of neurotrophic factors in depression.  Curr. Opin. Pharmacol. 7: 18-21.

Rantamäki, T., Hendolin, P., Kankaanpää, A., Mijatovic, J., Piepponen, P., Domenici, E., Chao, M.V., Männistö, P.T., and Castrén, E.  (2007). Pharmacologically diverse antidepressants rapidly activate Brain-derived neurotrophic factor (BDNF) receptor trkB and induce phospholipase-Cγ signaling pathways in mouse brain.  Neuropsychopharmacology 32: 2152–2162.

Sairanen, M., O’Leary, O.F., Knuuttila, J.E., and Castrén, E. (2007). Chronic antidepressant treatment selectively increases expression of plasticity-related proteins in the hippocampus and medial prefrontal cortex of the rat.  Neuroscience 144: 368–374.