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

Neuronal plasticity, essential for learning and memory, involves structural changes triggered by neurotrophic factors such as brain-derived neurotrophic factor (BDNF). BDNF activates its receptor, TrkB, to induce local and long-distance signaling, promoting dendritic branching. While BDNF activation of the mechanistic target of rapamycin (mTOR) pathway is well-documented in dendritic spines, its role in axons remains unclear. Using compartmentalized cultures of embryonic cortical neurons from mice, this study demonstrates that axonal BDNF triggers mTOR-dependent phosphorylation of translation regulators (4E-BP1 and S6), driving local protein synthesis. Fluorescent labeling, immunostaining, and radial microfluidic chambers were employed to isolate axonal compartments and assess local translation. Axonal BDNF increased Rab5 protein translation in a TrkB- and mTOR-dependent manner, highlighting the importance of localized protein synthesis for axonal trafficking.

Furthermore, axonal protein synthesis was required for retrograde transport of internalized cargoes and CREB activation in the nucleus, linking local translation to long- distance signaling. These findings highlight the crucial role of axonal mTOR activation in regulating local proteostasis and neuronal function, offering new insights into axonal trafficking mechanisms and their implications for neuroplasticity. This work advances our understanding of how mTOR activation in axons and localized translation induced by BDNF are essential for axonal transport and efficient signaling in cortical neurons.