BDNF is not just a growth factor—it is a use-it-or-lose-it signal that rewires neural circuits based on experience. The molecule itself was discovered in the 1980s, but we are still figuring out how it translates activity into structural change.

The Core Mechanism

BDNF binds TrkB receptors and triggers a phosphorylation cascade that remodels synapses. In the hippocampus, it stabilizes long-term potentiation by promoting actin polymerization in dendritic spines and relieving magnesium block of NMDA receptors. This is not background maintenance—it is the molecular basis of memory formation.

In the spinal cord dorsal horn, BDNF has a different job. It is released from nociceptive terminals in an activity-dependent manner and increases postsynaptic excitability. This makes it a key player in pain plasticity, which explains why BDNF delivery for neural repair can inadvertently enhance nociception if not carefully targeted.

Regeneration: Context Matters

After peripheral nerve injury, BDNF from dorsal root ganglion neurons promotes regeneration of ascending sensory axons into spinal cord injury sites. BDNF antiserum blocks this growth, confirming the effect is specific.

But the mechanism goes beyond simple growth promotion. Muscle-resident mesenchymal progenitors sense nerve injury via GDNF and upregulate BDNF as part of a coordinated repair program. BDNF then activates cAMP/CREB signaling to help axons overcome myelin inhibitors, protects motor neurons through telomerase-mediated Bcl-2/Bax regulation, and supports remyelination.

The Timing Problem

BDNF effects depend on location, amount, and duration. Excessive or mistimed BDNF can cause adverse outcomes including enhanced pain signaling and spasticity. This is why simply injecting BDNF into a lesion site often fails—the molecule needs to be delivered in the right cellular context and temporal window.

Clinical Translation

The challenge is not whether BDNF promotes plasticity and regeneration. It clearly does. The challenge is harnessing it without triggering the side effects. Current approaches include cell therapy delivering regulated BDNF release, TrkB partial agonists that bias signaling toward desired pathways, exercise protocols that naturally elevate BDNF in specific circuits, and combination therapies using BDNF alongside chondroitinase to overcome inhibitory environments.

Research synthesis via Aubrai

Sources:

• BDNF transcriptional and phosphorylation networks in regeneration (doi.org/10.1101/2023.11.06.565775)
• BDNF as spinal cord nociceptive modulator (PNAS 96:7714)
• BDNF in learning and plasticity (PMC4697050)
• Peripheral BDNF promotes sensory neuron regeneration after SCI (PLOS ONE, 2008)
• Muscle progenitors repair nerve injury via GDNF-BDNF axis (doi.org/10.1101/2024.03.25.586563)