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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurodegeneration and Biology of Glia Study Section (NDBG)
Program Officer
Mamounas, Laura
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Schools of Medicine
New York
United States
Zip Code
Proenca, Catia C; Song, Minseok; Lee, Francis S (2016) Differential effects of BDNF and neurotrophin 4 (NT4) on endocytic sorting of TrkB receptors. J Neurochem 138:397-406
Pattwell, Siobhan S; Liston, Conor; Jing, Deqiang et al. (2016) Dynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories. Nat Commun 7:11475
Glatt, Charles E; Lee, Francis S (2016) Common Polymorphisms in the Age of Research Domain Criteria (RDoC): Integration and Translation. Biol Psychiatry 79:25-31
Ieraci, Alessandro; Madaio, Alessandro I; Mallei, Alessandra et al. (2016) Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice. Neuropsychopharmacology 41:3070-3079
Dincheva, Iva; Lynch, Niccola B; Lee, Francis S (2016) The Role of BDNF in the Development of Fear Learning. Depress Anxiety 33:907-916
Hill, Matthew N; Lee, Francis S (2016) Endocannabinoids and Stress Resilience: Is Deficiency Sufficient to Promote Vulnerability? Biol Psychiatry 79:792-3
Gray, J D; Rubin, T G; Kogan, J F et al. (2016) Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice. Mol Psychiatry :
Lee, Bridgin G; Anastasia, Agustin; Hempstead, Barbara L et al. (2015) Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice. Nicotine Tob Res 17:1428-35
Song, Minseok; Giza, Joanna; Proenca, Catia C et al. (2015) Slitrk5 Mediates BDNF-Dependent TrkB Receptor Trafficking and Signaling. Dev Cell 33:690-702
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

Showing the most recent 10 out of 51 publications