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

Abstract

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 (BDNFMet), 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 BDNFMet is secreted in an activity-dependent manner. The nature of the cellular defect when both BDNFMet, and wild-type BDNF (BDNFval) 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 BDNFMet on BDNFval intracellular trafficking and processing. Our data indicate that abnormal trafficking of BDNF Met occurred only in neuronal and neurosecretory cells and that BDNFMet could alter the intracellular distribution and activity-dependent secretion of BDNFval. We determined that, when coexpressed in the same cell, ∼70% of the variant BDNF forms BDNF val·BDNFMet 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 BDNFMet or the BDNFval·BNFMet 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.