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Science 314 (5796): 140-143

Copyright © 2006 by the American Association for the Advancement of Science

Genetic Variant BDNF (Val66Met) Polymorphism Alters Anxiety-Related Behavior

Zhe-Yu Chen,1,4{dagger} Deqiang Jing,1* Kevin G. Bath,1* Alessandro Ieraci,1 Tanvir Khan,1 Chia-Jen Siao,2 Daniel G. Herrera,1 Miklos Toth,3 Chingwen Yang,5 Bruce S. McEwen,6 Barbara L. Hempstead,2 Francis S. Lee1,3{dagger}

Abstract: A common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, a methionine (Met) substitution for valine (Val) at codon 66 (Val66Met), is associated with alterations in brain anatomy and memory, but its relevance to clinical disorders is unclear. We generated a variant BDNF mouse (BDNFMet/Met) that reproduces the phenotypic hallmarks in humans with the variant allele. BDNFMet was expressed in brain at normal levels, but its secretion from neurons was defective. When placed in stressful settings, BDNFMet/Met mice exhibited increased anxiety-related behaviors that were not normalized by the antidepressant, fluoxetine. A variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.

1 Department of Psychiatry, Weill Medical College of Cornell University, New York, NY 10021, USA.
2 Division of Hematology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
3 Department of Pharmacology, Weill Medical College of Cornell University, New York, NY 10021, USA.
4 School of Medicine, Shandong University, Jinan, Shandong 250012, People's Republic of China.
5 Gene Targeting Facility, The Rockefeller University, New York, NY 10021, USA.
6 Laboratory of Neuroendocrinology, The Rockefeller University, New York, NY 10021, USA.

* These authors contributed equally to this work

{dagger} To whom correspondence should be addressed. E-mail: zheyuchen{at} (Z.-Y.C.); fslee{at} (F.S.L.)

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