title: Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants.
abstract: Brain-derived neurotrophic factor (BDNF) plays important roles in cell survival, neural plasticity, learning, and stress regulation. However, whether the recently found human BDNF Val66Met (BDNF(Met)) polymorphism could alter stress vulnerability remains controversial. More importantly, the molecular and structural mechanisms underlying the interaction between the BDNF(Met) polymorphism and stress are unclear. We found that heterozygous BDNF(+/Met) mice displayed hypothalamic-pituitary-adrenal axis hyperreactivity, increased depressive-like and anxiety-like behaviors, and impaired working memory compared with WT mice after 7 d restraint stress. Moreover, BDNF(+/Met) mice exhibited more prominent changes in BDNF levels and apical dendritic spine density in the prefrontal cortex and amygdala after stress, which correlated with the impaired working memory and elevated anxiety-like behaviors. Finally, the depressive-like behaviors in BDNF(+/Met) mice could be selectively rescued by acute administration of desipramine but not fluoxetine. These data indicate selective behavioral, molecular, and structural deficits resulting from the interaction between stress and the human genetic BDNF(Met) polymorphism. Importantly, desipramine but not fluoxetine has antidepressant effects on BDNF(+/Met) mice, suggesting that specific classes of antidepressant may be a more effective treatment option for depressive symptoms in humans with this genetic variant BDNF.
authors.affiliation: Department of Neurobiology, Shandong University, Jinan, Shandong, Peoples Republic of China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.forename: Dong-Dong
authors.initials: DD
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Ting
authors.initials: T
authors.lastname: Liu
authors.forename: Francis S
authors.initials: FS
authors.lastname: Lee
authors.forename: Zhe-Yu
authors.initials: ZY
authors.lastname: Chen
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics / Q000502:physiology; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000097:blood; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D003863:Depression / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005518:Food Preferences / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008715:Methionine / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism; D017966:Pyramidal Cells / Q000378:metabolism / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D016622:Silver Staining; D013315:Stress, Psychological / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D013550:Swimming / Q000523:psychology; D014633:Valine / Q000235:genetics*
chemical_list: D000928:Antidepressive Agents; D019208:Brain-Derived Neurotrophic Factor; C086924:Elk3 protein, mouse; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; D013549:Sweetening Agents; D013395:Sucrose; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D008715:Methionine; D014633:Valine; D003345:Corticosterone