title: Matrix Metalloprotease 3 Activity Supports Hippocampal EPSP-to-Spike Plasticity Following Patterned Neuronal Activity via the Regulation of NMDAR Function and Calcium Flux.
abstract: Matrix metalloproteases (MMPs) comprise a family of endopeptidases that are involved in remodeling the extracellular matrix and play a critical role in learning and memory. At least 24 different MMP subtypes have been identified in the human brain, but less is known about the subtype-specific actions of MMP on neuronal plasticity. The long-term potentiation (LTP) of excitatory synaptic transmission and scaling of dendritic and somatic neuronal excitability are considered substrates of memory storage. We previously found that MMP-3 and MMP-2/9 may be differentially involved in shaping the induction and expression of excitatory postsynaptic potential (EPSP)-to-spike (E-S) potentiation in hippocampal brain slices. MMP-3 and MMP-2/9 proteolysis was previously shown to affect the integrity or mobility of synaptic N-methyl-D-aspartate receptors (NMDARs) in vitro. However, the functional outcome of such MMP-NMDAR interactions remains largely unknown. The present study investigated the role of these MMP subtypes in E-S plasticity and NMDAR function in mouse hippocampal acute brain slices. The temporal requirement for MMP-3/NMDAR activity in E-S potentiation within the CA1 field largely overlapped, and MMP-3 but not MMP-2/9 activity was crucial for the gain-of-function of NMDARs following LTP induction. Functional changes in E-S plasticity following MMP-3 inhibition largely correlated with the expression of cFos protein, a marker of activity-related gene transcription. Recombinant MMP-3 promoted a gain in NMDAR-mediated field potentials and somatodendritic Ca2+waves. These results suggest that long-term hippocampal E-S potentiation requires transient MMP-3 activity that promotes NMDAR-mediated postsynaptic Ca2+entry that is vital for the activation of downstream signaling cascades and gene transcription.
authors.affiliation: Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Chalubinskiego 3, Wroclaw, 50-368, Poland.|Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland.
authors.forename: Patrycja
authors.initials: P
authors.lastname: Brzdąk
authors.affiliation: Laboratory of Cell Biophysics, Department of Molecular and Cellular Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Włodarczyk
authors.affiliation: Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Chalubinskiego 3, Wroclaw, 50-368, Poland.|Department of Animal Molecular Physiology, Institute of Experimental Biology, Wroclaw University, Wroclaw, Poland.
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Mozrzymas
authors.affiliation: Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Chalubinskiego 3, Wroclaw, 50-368, Poland. tomasz.wojtowicz@umed.wroc.pl.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Wójtowicz
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism*; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D009924:Organ Culture Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse
keywords: E-S potentiation; Extracellular proteolysis; Hippocampus; Matrix metalloprotease; NMDAR; Synaptic plasticity