Activity-dependent regulation of BDNF and Arc: master genes in synaptic plasticity ( )

Transcription

1 Norwegian-Estonian Research Cooperation Programme Activity-dependent regulation of BDNF and Arc: master genes in synaptic plasticity ( ) Project promoter: Tallinn University of Technology Principal investigator: Tõnis Timmusk Donor project partner: University of Bergen Principal investigator: Clive R. Bramham Tallinn

2 Examples of the Variety of Nerve Cell Morphologies Found in the Human Nervous System PN01012.JPG

3 PN01040.JPG Neuroglial Cells

4 Neurotrophic hypothesis

5 In vertebrates, ~50% neurons are lost during development. Most of neurons die around the time when the targets are innervated Viktor Hamburger Rita Levi-Montalcini Joined Wash.U:

6 Lab of Molecular Neurobiology at TUT: gene regulation and signaling in the nervous system Model organisms: mice and men Genes: neurotrophic factors and their receptors Diseases: neuropsychiatric and neurodegenerative Potential drugs: neurotrophic factors

7 Why is the project needed? Modifiability of neuronal connectivity by formation of new synapses, and alteration of the strength and stability of existing synapses, is regarded as the main cellular basis for memory and long-term behavioral adaptations. The genes encoding neurotrophin BDNF and activity-regulated cytoskeletonassociated protein ARC are considered to be the master genes of synaptic plasticity. Knowledge about the regulatory mechanisms of BDNF and ARC gene is important both for understanding of molecular basis of learning and memory and for finding new drug targets for the treatment of several nervous system diseases.

8 Neurodegenerative diseases and neurotrophic factors caudate nucleus and putamen BDNF GDNF, NRTN, BDNF, CDNF substantia nigra HD normal PD normal hippocampus and cerebral cortex 6-OHDA GDNF CDNF NGF, BDNF GDNF, BDNF spinal cord normal AD normal ALS Stephen Hawking

9 What were the objectives of the project? We aim to understand how synapses, the junctions across which a nerve impulse passes from an axon terminal to another neuron, function. More specifically, to study: (1) Regulation of BDNF gene transcription by its receptor TrkB signaling (2) Regulation of BDNF and Arc translatability by membrane depolarization and TrkB signaling BDNF hypothesis of synaptic consolidation. C.R. Bramham, E. Messaoudi / Progress in Neurobiology 76 (2005)

10 How to establish the cooperation? Previous cooperation Match making event under the Programme Embassy assistance Norwegian Helsinki Committee assistance Independent search for partner Programme / Fund operator Other

11 The role of the Norwegian partner in the project. What will the partnership achieve? Prof. Clive Bramham lab at University of Bergen possesses complementary high-level expertise and infrastructure as compared to Prof. Timmusk lab at Tallinn University of Technology, which covers a broad spectrum from molecular and cellular processes to assessment of synaptic plasticity and behavior of model animals. The coordinated application of this human capacity and methodological arsenal has facilitated integrative studies, leading to better understanding of the complexity of the brain. Prof. Clive Bramham lab was involved in many projects, particularly in electrophysiology and in vivo studies. Electrophysiology expertise is totally lacking in Estonian science and therefore this project has allowed Estonian scientists to learn methods of this important field of neuroscience. It is also expected, that members of Timmusk lab will carry out postdoctoral training in this field in Prof. Clive Bramham lab.

12 How was the cooperation carried out? The different but complementary expertise of Tallinn and Bergen research groups has enabled carry out this project. Project partner s main technical/professional contribution to the project was planning and carrying out experiments, particularly the in vivo animal experiments. The partnership has significantly contributed to strengthening bilateral relations between the partner labs by several visits, Skype conferences and correspondence that enabled discussions of project experimental plans and results. Importantly, the project partnership has helped to start to build up wider international cooperation in the field of neurotrophins and synaptic plasticity. The project sustainability is very good since many collaborative experiments are ongoing and several articles are planned to be published based on the results obtained. Joint proposals are planned to be submitted to European financing initiatives.

13 Main participants, including doctoral and master s students (Estonia) 1. Indrek Koppel, PhD 2. Mari Sepp, PhD 3. Kaur Jaanson, doctoral student, obtained PhD during the project 4. Kristi Luberg, doctoral student, obtained PhD during the project 5. Hanna Vihma, doctoral student, obtained PhD after the project 6. Jürgen Tuvikene, doctoral student 7. Laura Tamberg, doctoral student 8. Eli-Eelika Esvald, Master s student, currently doctoral student 9. Alex Sirp, Master s student, currently doctoral student 10. Tõnis Timmusk, PhD, professor, principal investigator

14 What did the project achieve? The results of the present research proposal about the regulatory mechanisms of BDNF and Arc genes will help to better understand the development and functioning of nervous system. Dysregulation of BDNF levels and/or its receptor TrkB activity are accompanied by and are believed to lead to several pathologies, particularly nervous system diseases like neurodegenerative, psychiatric and cognitive diseases. It is widely accepted that signaling of BDNF is involved in the mechanism of action of many drugs and that the BDNF protein could be a powerful drug. Knowledge about the regulatory mechanisms of BDNF gene could also lead to the development of drugs for treatment of patients suffering from these diseases. The project has had positive impact on the internationalization of R&D and higher education.

15 Publication 1 in Journal of Neurochemistry

16 Publication 2 in The Journal of Neuroscience

17 Publication 3 in Glia

18 Other publications 1. Nair RR, Patil S, Tiron A, Kanhema T, Panja D, Schiro L, Parobczak K, Wilczynski G, Bramham CR. Dynamic Arc SUMOylation and Selective Interaction with F-Actin-Binding Protein Drebrin A in LTP Consolidation In Vivo. Front Synaptic Neurosci May 10;9:8. 2. Nikolaienko O, Eriksen MS, Patil S, Bito H, Bramham CR. Stimulus-evoked ERK-dependent phosphorylation of activity-regulated cytoskeleton-associated protein (Arc) regulates its neuronal subcellular localization. Neuroscience Sep 30;360: Esvald E. E., Tuvikene J., Sirp A., Patil S., Bramham C. R. CREB and BDNF transcriptional autoregulation. Manuscript to be submitted in 2018 to The Journal of Neuroscience.

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