Distinct 3′UTRs differentially regulate activity-dependent translation of brain-derived neurotrophic factor (BDNF)

Abstract

Expression of the brain-derived neurotrophic factor (BDNF) is under tight regulation to accommodate its intricate roles in controlling brain function. Transcription of BDNF initiates from multiple promoters in response to distinct stimulation cues. However, regardless which promoter is used, all BDNF transcripts are processed at two alternative polyadenylation sites, generating two pools of mRNAs that carry either a long or a short 3′UTR, both encoding the same BDNF protein. Whether and how the two distinct 3′UTRs may differentially regulate BDNF translation in response to neuronal activity changes is an intriguing and challenging question. We report here that the long BDNF 3′UTR is a bona fide cis-acting translation suppressor at rest whereas the short 3′UTR mediates active translation to maintain basal levels of BDNF protein production. Upon neuronal activation, the long BDNF 3′UTR, but not the short 3′UTR, imparts rapid and robust activation of translation from a reporter. Importantly, the endogenous long 3′UTR BDNF mRNA specifically undergoes markedly enhanced polyribosome association in the hippocampus in response to pilocarpine induced-seizure before transcriptional up-regulation of BDNF. Furthermore, BDNF protein level is quickly increased in the hippocampus upon seizure-induced neuronal activation, accompanied by a robust activation of the tropomyosin-related receptor tyrosine kinase B. These observations reveal a mechanism for activity-dependent control of BDNF translation and tropomyosin-related receptor tyrosine kinase B signaling in brain neurons.