Abstract
Highly specific activity-dependent neuronal responses are necessary for modulating synapses to facilitate learning and memory. We present evidence linking a number of important processes involved in regulating synaptic plasticity, suggesting a mechanistic pathway whereby activity-dependent signaling, likely through protein kinase C (PKC)-mediated phosphorylation of HuD, can relieve basal repression of Bdnf mRNA translation in dendrites, allowing for increased TrkB signaling and synaptic remodeling. We demonstrate that the neuronal ELAV family of RNA binding proteins associates in vivo with several Bdnf mRNA isoforms present in the adult brain in an activity-dependent manner, and that one member, HuD, interacts directly with sequences in the long Bdnf 3' untranslated region (3'UTR) and co-localizes with Bdnf mRNA in dendrites of hippocampal neurons. Activation of PKC leads to increased dendritic translation of mRNAs containing the long Bdnf 3'UTR, a process that is dependent on the presence of HuD and its phosphorylation at threonine residues 149 and/or 165. Thus, we found a direct effect of HuD on regulating translation of dendritic Bdnf mRNAs to mediate local and activity-dependent increases in dendritic BDNF synthesis.
Highlights
Brain-derived neurotrophic factor (BDNF) is an important molecule involved in learning and memory in the adult brain, with demonstrated roles in regulating synaptic plasticity [1,2,3]
Neuronal Hu proteins are associated with Bdnf mRNAs in the mouse forebrain Mouse Bdnf mRNAs can have either a short (0.35 kb) or long (2.85 kb) 3' untranslated region (3' UTR), depending on which of two polyadenylation sites is used for processing [24]
The neuronal ELAV family of RNA-binding proteins (RBPs), consisting of HuB, HuC and HuD, has been previously demonstrated to interact with several mRNAs to regulate their expression [21,25,26], and putative binding sites for these proteins are present within the long Bdnf 3' UTR, making them potential candidates for the trans-acting factors regulating local BDNF synthesis
Summary
Brain-derived neurotrophic factor (BDNF) is an important molecule involved in learning and memory in the adult brain, with demonstrated roles in regulating synaptic plasticity [1,2,3]. The mechanisms by which BDNF regulates synaptic strength have become increasingly well understood. BDNF stored in dendritic vesicles is released both constitutively and through an activity-dependent pathway. Released BDNF can potentially bind to TrkB receptors on both preand post-synaptic terminals, leading to retrograde and anterograde signaling [4,5,6,7]. Recent studies highlight the significance of regulation of local translation of mRNAs in activated spines as one way in which BDNF can modify synapses in response to stimulation [8,9,10,11]. Despite the increasing understanding of how a number of important genes are regulated by BDNF signaling to modify the structure and composition of synapses, less is known
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