ROLE OF HUD IN REGULATING LOCAL DENDRITIC TRANSLATION OF LONG BDNF 3'UTR TRANSCRIPTS
Highly specific activity-dependent neuronal responses are necessary for modulating synapses to facilitate learning and memory. I present evidence linking a number of important processes involved in regulating synaptic plasticity, suggesting a mechanistic pathway whereby activity-dependent signaling, through PKC-mediated phosphorylation of HuD, can relieve basal repression of Bdnf mRNA translation in dendrites, allowing for increased TrkB signaling and synaptic remodeling. I demonstrate that the neuronal ELAV (nELAV) 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. HuD is a repressor of translation for dendritic mRNAs containing the long Bdnf 3'UTR, and activation of PKC can relieve this repression, a process that may depend on phosphorylation of HuD at threonine residues 149 and/or 165. I did not detect a role for HuD expression in the trafficking of Bdnf mRNAs to dendritic compartments, indicating a direct effect of HuD on regulating translation of dendritic Bdnf mRNAs to mediate local and activity-dependent increases in dendritic BDNF synthesis. Furthermore, mice that do not produce long Bdnf 3'UTR mRNAs are impaired in a spatial memory task, indicating that regulatory elements present in this region are important for mediating BDNF-dependent learning and memory.
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