Matrix Metalloproteinase-9 controls structural synaptic plasticity via BDNF-dependent signaling.

Structural long-term potentiation (sLTP), an activity-dependent growth of dendritic spines that harbor excitatory synapses, is a major form of synaptic plasticity in learning and memory processes. The spine enlargement is influenced by the extracellular matrix and its proteolytic enzymes, among which matrix metalloproteinase 9 (MMP-9) is a prominent example. Here, we utilized two-photon microscopy and two-photon glutamate uncaging to demonstrate that MMP-9 activity is essential for sLTP and is rapidly (∼seconds) released from dendritic spines in response to synaptic stimulation. MMP-9 has been postulated to play a pivotal role in the maturation of brain-derived neurotrophic factor (BDNF), a major protein involved in LTP that acts on TrkB receptor. We show that chemically or genetically inhibiting MMP-9 impairs TrkB activation, as measured by fluorescence lifetime imaging microscopy of FRET sensor. Furthermore, we provide evidence for in vitro cleavage of proBDNF into mature BDNF by MMP-9. Our findings point to autocrine mechanism of action of MMP-9 through BDNF maturation and TrkB activation during sLTP.