Brain derived neurotrophic factor (BDNF) plays critical roles in vertebrate nervous system development and function. Recently, a single nucleotide polymorphism (Val66Met) in the BDNF gene leading to a prodomain substitution at position 66 from a valine (Val) to methionme (Met) has been shown to lead in humans to hippocampal dependent memory impairments and susceptibility to neuropsychiatric disorders. This BDNF polymorphism represents the first alteration in a neurotrophin that has been linked to clinical pathology. Less is known about the molecular mechanisms underlying altered variant BDNF (BDNFMet) functioning. When overexpressed in hippocampal neurons, BDNFMet has reduced activity dependent secretion, suggesting the presence of a specific signal in the BDNF prodomain that is required for efficient BDNF trafficking to the regulated secretory pathway. Preliminary studies suggest the hypothesis that BDNFMet aberrantly engages the highly specialized biochemical mechanisms that regulate BDNF trafficking to secretory pathways, which are critical determinants of BDNF's biological responses. The proposed studies are designed to identify specific proteins that regulate aberrant BDNFMet trafficking, and to examine the in vivo consequences on hippocampal structure and function. Experiments in this proposal will primarily utilize a novel transgenic knock-in mouse expressing an epitope tagged version of variant BDNF (BDNF 9 e) to enable assessment of BDNFMet trafficking events under endogenously expressed conditions and analysis of in vivo consequences on hippocampal structure and function.
The Specific Aims of the proposed studies are to 1) define the trafficking defect and functional consequences in neurons endogenously expressing BDNFMet, 2) identify proteins that are involved in aberrant BDNFMet trafficking, and 3) determine the in vivo consequences of BDNFMet on hippocampal function. These studies will contribute to a fundamental molecular understanding of the mechanisms that underlie aberrant BDNFMet trafficking in neurons, and directly address the physiological relevance of this variant BDNF on hippocampal function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS052819-09
Application #
8453436
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Mamounas, Laura
Project Start
2005-06-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
9
Fiscal Year
2013
Total Cost
$325,219
Indirect Cost
$132,782
Name
Weill Medical College of Cornell University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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Dincheva, Iva; Drysdale, Andrew T; Hartley, Catherine A et al. (2015) FAAH genetic variation enhances fronto-amygdala function in mouse and human. Nat Commun 6:6395

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