UC San Diego

Over the past few decades, brain-derived neurotrophic factor (BDNF)— a member of a small family of secreted proteins called neurotrophins— has emerged as a crucial regulator of almost all stages of neuronal circuit development, including axonal specification and neurite growth. Nonetheless, details regarding the spatiotemporal regulation of BDNF-induced axonal growth and underlying mechanisms remain poorly understood. Here, we show that BDNF signals locally in distal axons of hippocampal neurons to rapidly increase axonal elongation rates, whereas BDNF signaling in somatodendritic compartments does not increase distal axon growth. We found that BDNF signals through TrkB receptors in axons to locally activate the mTOR/S6K signaling pathway and intra-axonal protein synthesis. Our findings point to a mechanism whereby local BDNF signaling in axons induces: (1) an early growth response, noticeable within the first 10 min of axonal exposure to BDNF, which requires intra-axonal protein synthesis and local mTOR activity, and (2) a sustained growth response, which occurs 60 min or longer after initial exposure to BDNF, and requires new transcription and translation in neuronal cell bodies. Given the requirement for new transcription to sustain BDNF-induced axonal growth, in Chapter 3 we explored transcriptional changes following BDNF stimulation of hippocampal neurons in mass cultures or compartmentalized microfluidic cultures. We describe dynamic changes in the expression of select transcripts resulting from global and/or axonal BDNF signaling. Taken together, these results provide mechanistic insights into BDNF-induced axonal growth in hippocampal neurons.