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The Journal of Neuroscience, May 5, 2004, 24(18):4401-4411; doi:10.1523/JNEUROSCI.0348-04.2004

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Cellular/Molecular
Variant Brain-Derived Neurotrophic Factor (BDNF) (Met66) Alters the Intracellular Trafficking and Activity-Dependent Secretion of Wild-Type BDNF in Neurosecretory Cells and Cortical Neurons

Zhe-Yu Chen,^1,3 Paresh D. Patel,⁴ Gayatree Sant,¹ Chui-Xiang Meng,⁵ Kenneth K. Teng,² Barbara L. Hempstead,² and Francis S. Lee¹

¹Department of Psychiatry and Pharmacology and ²Division of Hematology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, ³Department of Neurobiology, the Second Military Medical University, Shanghai 200433, China, ⁴Mental Health Research Institute and Department of Psychiatry, The University of Michigan Medical School, Ann Arbor, Michigan 48109, and ⁵Department of Basic Medical Sciences, the Second Military Medical University, Shanghai 200433, China

Brain-derived neurotrophic factor (BDNF) plays a critical role in nervous system and cardiovascular development and function. Recently, a common single nucleotide polymorphism in the bdnf gene, resulting in a valine to methionine substitution in the prodomain (BDNF_Met), has been shown to lead to memory impairment and susceptibility to neuropsychiatric disorders in humans heterozygous for the variant BDNF. When expressed by itself in hippocampal neurons, less BDNF_Met is secreted in an activity-dependent manner. The nature of the cellular defect when both BDNF_Met and wild-type BDNF (BDNF_Val) are present in the same cell is not known. Given that this is the predominant expression profile in humans, we examined the effect of coexpressed BDNF_Met on BDNF_Val intracellular trafficking and processing. Our data indicate that abnormal trafficking of BDNF_Met occurred only in neuronal and neurosecretory cells and that BDNF_Met could alter the intracellular distribution and activity-dependent secretion of BDNF_Val. We determined that, when coexpressed in the same cell, 70% of the variant BDNF forms BDNF_Val·BDNF_Met heterodimers, which are inefficiently sorted into secretory granules resulting in a quantitative decreased secretion. Finally, we determined the form of BDNF secreted in an activity-dependent manner and observed no differences in the forms of BDNF_Met or the BDNF_Val·BDNF_Met heterodimer compared with BDNF_Val. Together, these findings indicate that components of the regulated secretory machinery interacts specifically with a signal in the BDNF prodomain and that perturbations in BDNF trafficking may lead to selective impairment in CNS function.

Key words: brain derived neurotrophic factor; polymorphism; prodomain; proneurotrophin; intracellular trafficking; regulated secretion

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Received Oct 17, 2003; revised March 23, 2004; accepted March 23, 2004.

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