The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function.
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.
Egan
Michael F
MF
Clinical Brain Disorders Branch, National Institute of Mental Health, Room 4s-235, 10 Center Drive, Bethesda, MD 20892, USA.
Kojima
Masami
M
Callicott
Joseph H
JH
Goldberg
Terry E
TE
Kolachana
Bhaskar S
BS
Bertolino
Alessandro
A
Zaitsev
Eugene
E
Gold
Bert
B
Goldman
David
D
Dean
Michael
M
Lu
Bai
B
Weinberger
Daniel R
DR
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*
D019208:Brain-Derived Neurotrophic Factor; D001224:Aspartic Acid; C000179:N-acetylaspartate; D008715:Methionine; D014633:Valine