Impact of genetic variant BDNF (Val66Met) on brain structure and function.
A common single-nucleotide polymorphism in the human 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 (BDNF(MET/Met)) that reproduces the phenotypic hallmarks in humans with the variant allele. Variant BDNF(Met) was expressed in brain at normal levels, but its secretion from neurons was defective. In this context, the BDNF(Met/Met) mouse represents a unique model that directly links altered activity-dependent release of BDNF to a defined set of in vivo consequences. Our subsequent analyses of these mice elucidated a phenotype that had not been established in human carriers: increased anxiety. When placed in conflict settings, BDNF(Met/Met) mice display increased anxiety-related behaviours that were not normalized by the antidepressant, fluoxetine. A genetic variant BDNF may thus play a key role in genetic predispositions to anxiety and depressive disorders.
Chen
Zhe-Yu
ZY
Department of Psychiatry, Weill Medical College of Cornell University, New York, NY 10021, USA.
Bath
Kevin
K
McEwen
Bruce
B
Hempstead
Barbara
B
Lee
Francis
F
D019943:Amino Acid Substitution; D000818:Animals; D001008:Anxiety Disorders / Q000235:genetics*; D001921:Brain / Q000033:anatomy & histology* / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003866:Depressive Disorder / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006133:Growth Substances / Q000502:physiology; D006801:Humans; D001523:Mental Disorders / Q000235:genetics*; D008715:Methionine; D051379:Mice; D008822:Mice, Transgenic; D020641:Polymorphism, Single Nucleotide; D011618:Psychotic Disorders / Q000235:genetics; D014633:Valine
D019208:Brain-Derived Neurotrophic Factor; D006133:Growth Substances; D008715:Methionine; D014633:Valine