title: Mechanisms of NMDA Receptor- and Voltage-Gated L-Type Calcium Channel-Dependent Hippocampal LTP Critically Rely on Proteolysis That Is Mediated by Distinct Metalloproteinases.
abstract: Long-term potentiation (LTP) is widely perceived as a memory substrate and in the hippocampal CA3-CA1 pathway, distinct forms of LTP depend on NMDA receptors (nmdaLTP) or L-type voltage-gated calcium channels (vdccLTP). LTP is also known to be effectively regulated by extracellular proteolysis that is mediated by various enzymes. Herein, we investigated whether in mice hippocampal slices these distinct forms of LTP are specifically regulated by different metalloproteinases (MMPs). We found that MMP-3 inhibition or knock-out impaired late-phase LTP in the CA3-CA1 pathway. Interestingly, late-phase LTP was also decreased by MMP-9 blockade. When both MMP-3 and MMP-9 were inhibited, both early- and late-phase LTP was impaired. Using immunoblotting, in situ zymography, and immunofluorescence, we found that LTP induction was associated with an increase in MMP-3 expression and activity in CA1 stratum radiatum. MMP-3 inhibition and knock-out prevented the induction of vdccLTP, with no effect on nmdaLTP. L-type channel-dependent LTP is known to be impaired by hyaluronic acid digestion. We found that slice treatment with hyaluronidase occluded the effect of MMP-3 blockade on LTP, further confirming a critical role for MMP-3 in this form of LTP. In contrast to the CA3-CA1 pathway, LTP in the mossy fiber-CA3 projection did not depend on MMP-3, indicating the pathway specificity of the actions of MMPs. Overall, our study indicates that the activation of perisynaptic MMP-3 supports L-type channel-dependent LTP in the CA1 region, whereas nmdaLTP depends solely on MMP-9.
  
  
  
  Various types of long-term potentiation (LTP) are correlated with distinct phases of memory formation and retrieval, but the underlying molecular signaling pathways remain poorly understood. Extracellular proteases have emerged as key players in neuroplasticity phenomena. The present study found that L-type calcium channel-dependent LTP in the CA3-CA1 hippocampal projection is critically regulated by the activity of matrix metalloprotease 3 (MMP-3), in contrast to NMDAR-dependent LTP regulated by MMP-9. Moreover, the induction of LTP was associated with an increase in MMP-3 expression and activity. Finally, we found that the digestion of hyaluronan, a principal extracellular matrix component, disrupted the MMP-3-dependent component of LTP. These results indicate that distinct MMPs might act as molecular switches for specific types of LTP.
authors.affiliation: Laboratory of Animal Molecular Physiology, Department of Biological Sciences, Wroclaw University, 50-205, Wroclaw, Poland, grzegorz.wiera@uwr.edu.pl jerzy.mozrzymas@umed.wroc.pl.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Wiera
authors.affiliation: Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, 50-368, Wroclaw, Poland.
authors.forename: Daria
authors.initials: D
authors.lastname: Nowak
authors.affiliation: Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, 3000 Leuven, Belgium, and.
authors.forename: Inge
authors.identifier: 0000-0002-3125-0438
authors.initials: I
authors.lastname: van Hove
authors.affiliation: Department of Histology and Embryology, Wroclaw Medical University, 50-368, Wroclaw, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Dziegiel
authors.affiliation: Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, 3000 Leuven, Belgium, and.
authors.forename: Lieve
authors.identifier: 0000-0003-0186-1411
authors.initials: L
authors.lastname: Moons
authors.affiliation: Laboratory of Animal Molecular Physiology, Department of Biological Sciences, Wroclaw University, 50-205, Wroclaw, Poland, grzegorz.wiera@uwr.edu.pl jerzy.mozrzymas@umed.wroc.pl.|Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, 50-368, Wroclaw, Poland.
authors.forename: Jerzy W
authors.initials: JW
authors.lastname: Mozrzymas
mesh_terms: D000818:Animals; D056547:CA1 Region, Hippocampal / Q000187:drug effects; D056654:CA3 Region, Hippocampal / Q000187:drug effects; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects*; D006820:Hyaluronic Acid / Q000494:pharmacology; D006821:Hyaluronoglucosaminidase / Q000494:pharmacology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000187:drug effects*; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D045726:Metalloproteases / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019599:Mossy Fibers, Hippocampal / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D059748:Proteolysis; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects* / Q000235:genetics / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D016194:Receptors, N-Methyl-D-Aspartate; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; D045726:Metalloproteases; D019278:Matrix Metalloproteinase 3; C511769:Mmp3 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
keywords: L-type calcium channels; extracellular matrix; long-term potentiation; matrix metalloproteinase; proteolysis; synaptic plasticity