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

1. 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 Laulasmaa 21.09.2017

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

3. Neurotrophic hypothesis

4. In vertebrates, ~50% neurons are lost during development. Most of neurons die around the time when the targets are innervated Rita Levi-Montalcini 1909-2012 Viktor Hamburger 1900-2001 Joined Wash.U: 1934 1947

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

6. 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 cytoskeleton-associated 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.

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

8. What is the objective 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)

9. 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 neuro-degenerative, 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.

10. 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.

11. Publication 1 in Journal of Neurochemistry

12. Publication 2 in Journal of Neuroscience

13. 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. 2017 May 10;9:8. 2. Koppel I., Jaanson K., Klasche A., Tuvikene J., Tiirik T., Pärn A., Timmusk T. Dopamine cross-reacts with adrenoreceptors in cortical astrocytes to induce BDNF expression, CREB signaling and morphological transformation. Glia, 2017, in press. 3. 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. 2017 Sep 30;360:68-80.