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

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
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:

5. 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

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
BDNF
GDNF, NRTN, BDNF, CDNF
caudate nucleus and putamen
substantia nigra
HD normal
PD normal
hippocampus and cerebral cortex
6-OHDA GDNF CDNF
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
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 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 Sep 30;360:68-80.