BDNF-induced axonal mTOR activation promotes Rab5 translation, axonal transport, and CREB phosphorylation in cortical neurons.

Abstract

Brain-derived neurotrophic factor (BDNF) promotes neuronal plasticity through retrograde signaling from axon terminals to the nucleus, activating CREB-dependent transcription. While this relies on signaling endosomes, the molecular mechanisms enabling their axonal transport remain poorly understood. Using compartmentalized cultures of mouse cortical neurons, we show that axonal BDNF activates mTOR signaling and stimulates local protein synthesis. Translation inhibitors blocked both BDNF-enhanced retrograde transport and nuclear CREB phosphorylation, indicating that axonal protein synthesis is required for long-distance signaling. Among locally synthesized proteins, we identified Rab5, a master regulator of endosomal trafficking. BDNF increased axonal Rab5 levels through TrkB- and mTOR-dependent mechanisms, confirmed by puromycin-PLA for Rab5 and soma-free axon preparations. Axon-specific Rab5 knockdown abolished BDNF-induced retrograde transport and CREB activation, demonstrating that local axonal translation of Rab5 mRNA is essential for neurotrophin signaling propagation. Remarkably, even basal retrograde transport depended on ongoing axonal Rab5 synthesis, revealing a constitutive role for local translation in maintaining axonal trafficking capacity. These findings establish that local axonal translation of trafficking regulators is a prerequisite for axon-to-nucleus neurotrophin signaling, positioning on-demand protein synthesis as a central node in long-distance neuronal communication.