BDNF regulation of the cortical neuron transcriptome

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 DESCRIPTION (provided by applicant): Brain-derived neurotrophic factor (BDNF) is a secreted polypeptide growth factor that is a major regulator of synapse development and plasticity in the mammalian brain. As there is evidence for dysregulation of BDNF signaling in many neurodevelopmental, neurodegenerative, and psychiatric disorders, the regulatory pathways utilized by BDNF are believed relevant to the pathophysiology of these disorders. BDNF controls the formation of new synapses and modification of existing synapses in part through regulation of the transcription of specific messenger RNAs (mRNAs), the regulation of mRNA translation initiation, and the post-translational modulation of specific protein functions. I particular, the translation of new polypeptides from mRNA has been shown to be essential for effects of BDNF on synapse formation and learning and memory. However, the complete set of specific mRNAs subject to such regulation and the relevant regulatory mechanisms involved have not been fully determined. The objective of this proposal is to comprehensively identify the collection of mRNAs whose abundance and translation are acutely regulated by Brain-derived neurotrophic factor (BDNF) with a specific focus on inhibitory neurons, for which little is known regarding translation regulation. In parallel, we will identify microRNAs, an important class of regulatory RNAs, which are acutely regulated by BDNF in an effort to uncover mechanisms by which BDNF modulates mRNA abundance and translation. These datasets, obtained from both primary cultured neurons and genetically manipulated mice, will be analyzed with bioinformatic approaches to identify candidate BDNF- regulated pathways important in synapse development and function both in vitro and in vivo, and will ultimately serve as a useful resource for the fiel.