BDNF-driven synaptic plasticity requires autocrine matrix metalloproteinase-9 activity.

Structural plasticity of dendritic spines is a fundamental mechanism of learning and memory. It depends on the release of brain-derived neurotrophic factor (BDNF) and activation of its receptor, tropomyosin receptor kinase B (TrkB). However, to bind TrkB, BDNF requires proteolytic cleavage to its mature form. Here, we demonstrate that MMP-9, an extracellular protease essential for neuronal function, plays a key role in this process. We show that, like BDNF, MMP-9 is rapidly released in response to synaptic stimulation, and its proteolytic activity, restricted to the activated spine, can be detected as early as 2 min after stimulation. Using two-photon microscopy and single-spine stimulation by glutamate uncaging, we demonstrate that MMP-9 action is important for TrkB activation and is required for structural plasticity. Furthermore, we provide evidence for a direct cleavage of proBDNF into mature BDNF by MMP-9. Our findings reveal a critical interaction between MMP-9 and BDNF through their autocrine regulation of TrkB activation and dendritic spine structural changes.