title: The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.
abstract: Brain-derived neurotrophic factor (BDNF) modulates hippocampal plasticity and hippocampal-dependent memory in cell models and in animals. We examined the effects of a valine (val) to methionine (met) substitution in the 5' pro-region of the human BDNF protein. In human subjects, the met allele was associated with poorer episodic memory, abnormal hippocampal activation assayed with fMRI, and lower hippocampal n-acetyl aspartate (NAA), assayed with MRI spectroscopy. Neurons transfected with met-BDNF-GFP showed lower depolarization-induced secretion, while constitutive secretion was unchanged. Furthermore, met-BDNF-GFP failed to localize to secretory granules or synapses. These results demonstrate a role for BDNF and its val/met polymorphism in human memory and hippocampal function and suggest val/met exerts these effects by impacting intracellular trafficking and activity-dependent secretion of BDNF.
authors.affiliation: Clinical Brain Disorders Branch, National Institute of Mental Health, Room 4s-235, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Egan
authors.forename: Masami
authors.initials: M
authors.lastname: Kojima
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Callicott
authors.forename: Terry E
authors.initials: TE
authors.lastname: Goldberg
authors.forename: Bhaskar S
authors.initials: BS
authors.lastname: Kolachana
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bertolino
authors.forename: Eugene
authors.initials: E
authors.lastname: Zaitsev
authors.forename: Bert
authors.initials: B
authors.lastname: Gold
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Michael
authors.initials: M
authors.lastname: Dean
authors.forename: Bai
authors.initials: B
authors.lastname: Lu
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D000483:Alleles; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008568:Memory / Q000502:physiology*; D008715:Methionine / Q000235:genetics*; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D021381:Protein Transport; D022142:Secretory Vesicles / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D014633:Valine / Q000235:genetics*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D001224:Aspartic Acid; C000179:N-acetylaspartate; D008715:Methionine; D014633:Valine