title: Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately.
abstract: Persistent dendritic spine enlargement is associated with stable long-term potentiation (LTP), and the latter is thought to underlie long-lasting memories. Extracellular proteolytic remodeling of the synaptic microenvironment could be important for such plasticity, but whether or how proteolytic remodeling contributes to persistent modifications in synapse structure and function is unknown. Matrix metalloproteinase-9 (MMP-9) is an extracellular protease that is activated perisynaptically after LTP induction and required for LTP maintenance. Here, by monitoring spine size and excitatory postsynaptic potentials (EPSPs) simultaneously with combined 2-photon time-lapse imaging and whole-cell recordings from hippocampal neurons, we find that MMP-9 is both necessary and sufficient to drive spine enlargement and synaptic potentiation concomitantly. Both structural and functional MMP-driven forms of plasticity are mediated through beta1-containing integrin receptors, are associated with integrin-dependent cofilin inactivation within spines, and require actin polymerization. In contrast, postsynaptic exocytosis and protein synthesis are both required for MMP-9-induced potentiation, but not for initial MMP-9-induced spine expansion. However, spine expansion becomes unstable when postsynaptic exocytosis or protein synthesis is blocked, indicating that the 2 forms of plasticity are expressed independently but require interactions between them for persistence. When MMP activity is eliminated during theta-stimulation-induced LTP, both spine enlargement and synaptic potentiation are transient. Thus, MMP-mediated extracellular remodeling during LTP has an instructive role in establishing persistent modifications in both synapse structure and function of the kind critical for learning and memory.
authors.affiliation: Department of Neurology, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, NY 10029, USA.
authors.forename: Xiao-bin
authors.initials: XB
authors.lastname: Wang
authors.forename: Ozlem
authors.initials: O
authors.lastname: Bozdagi
authors.forename: Jessica S
authors.initials: JS
authors.lastname: Nikitczuk
authors.forename: Zu Wei
authors.initials: ZW
authors.lastname: Zhai
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhou
authors.forename: George W
authors.initials: GW
authors.lastname: Huntley
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D049229:Dendritic Spines / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D005109:Extracellular Matrix / Q000201:enzymology; D016023:Integrins / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism* / Q000494:pharmacology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051339:Actin Depolymerizing Factors; D000199:Actins; D016023:Integrins; D020780:Matrix Metalloproteinase 9