Author/Authors :
Michael F. Egan، نويسنده , , Masami Kojima، نويسنده , , Joseph H. Callicott، نويسنده , , Terry E. Goldberg، نويسنده , , Bhaskar S. Kolachana، نويسنده , , Alessandro Bertolino، نويسنده , , Eugene Zaitsev، نويسنده , , Bert Gold، نويسنده , , David Goldman، نويسنده , , J. Michael Dean، نويسنده , , Bai Lu، نويسنده , , Daniel R. Weinberger، نويسنده ,
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.
