Synaptic activity has a profound effect on the formation of appropriate connections in the brain. Work during the last decade has indicated that such activity-dependent plasticity requires calcium influx, which triggers a cascade of intracellular biochemical events that lead to long lasting physiological and anatomical changes. Many of these changes require calcium-dependent gene expression, and several lines of evidence suggest that the Brain-derived neurotophic factor (BDNF) gene is an important target of calcium signaling in neurons. The focus of the proposed experiments is to identify the mechanisms by which calcium influx leads to BDNF expression in cortical neurons. Our preliminary studies suggest that calcium- dependent expression of BDNF is regulated by two calcium-response elements. The first is a novel element (CRS-I) that is regulated by an as yet unidentified transcription factor. The second element is homologous to the cAMP response element (CRE) and is regulated by the transcription factor CREB. To gain further insight into the mechanisms by which calcium regulates BDNF expression, we propose to (i) identify and characterize the transcription factor that mediates transactivation via CRS-I, and (ii) determine the mechanism by which CRS-I and BIII-CRE cooperate to regulate BDNF expression. The mechanisms underlying activity-dependent BDNF expression are of scientific as well as clinical interest. It is clear that BDNF plays a critical role in brain development and plasticity, ans therefore perturbation of BDNF regulation might contribute to neurological and neuropsychiatric disorders. Our investigations should lead to the identification of molecules involved in regulating BDNF expression, and it is likely that this molecular understanding will eventually be useful in developing clinical strategies to correct disorders of the nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH060598-03
Application #
6477098
Study Section
Special Emphasis Panel (ZRG1-MDCN-6 (02))
Program Officer
Brady, Linda S
Project Start
1999-12-01
Project End
2004-11-30
Budget Start
2001-12-01
Budget End
2002-11-30
Support Year
3
Fiscal Year
2002
Total Cost
$269,582
Indirect Cost
Name
Johns Hopkins University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Chen, Yachi; Wang, Phyllis Y; Ghosh, Anirvan (2005) Regulation of cortical dendrite development by Rap1 signaling. Mol Cell Neurosci 28:215-28
Dijkhuizen, Paul A; Ghosh, Anirvan (2005) BDNF regulates primary dendrite formation in cortical neurons via the PI3-kinase and MAP kinase signaling pathways. J Neurobiol 62:278-88
Aizawa, Hiroyuki; Hu, Shu-Ching; Bobb, Kathryn et al. (2004) Dendrite development regulated by CREST, a calcium-regulated transcriptional activator. Science 303:197-202
Redmond, Lori; Kashani, Amir H; Ghosh, Anirvan (2002) Calcium regulation of dendritic growth via CaM kinase IV and CREB-mediated transcription. Neuron 34:999-1010