PMID- 28069922 OWN - NLM STAT- MEDLINE DCOM- 20170724 LR - 20200225 IS - 1529-2401 (Electronic) IS - 0270-6474 (Print) IS - 0270-6474 (Linking) VI - 37 IP - 5 DP - 2017 Feb 1 TI - Mechanisms of NMDA Receptor- and Voltage-Gated L-Type Calcium Channel-Dependent Hippocampal LTP Critically Rely on Proteolysis That Is Mediated by Distinct Metalloproteinases. PG - 1240-1256 LID - 10.1523/JNEUROSCI.2170-16.2016 [doi] AB - 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. SIGNIFICANCE STATEMENT: 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. CI - Copyright (c) 2017 the authors 0270-6474/17/371240-17$15.00/0. FAU - Wiera, Grzegorz AU - Wiera G AD - 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. FAU - Nowak, Daria AU - Nowak D AD - Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, 50-368, Wroclaw, Poland. FAU - van Hove, Inge AU - van Hove I AUID- ORCID: 0000-0002-3125-0438 AD - Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, 3000 Leuven, Belgium, and. FAU - Dziegiel, Piotr AU - Dziegiel P AD - Department of Histology and Embryology, Wroclaw Medical University, 50-368, Wroclaw, Poland. FAU - Moons, Lieve AU - Moons L AUID- ORCID: 0000-0003-0186-1411 AD - Neural Circuit Development and Regeneration Research Group, Department of Biology, KU Leuven, 3000 Leuven, Belgium, and. FAU - Mozrzymas, Jerzy W AU - Mozrzymas JW AD - 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. AD - Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, 50-368, Wroclaw, Poland. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20170109 PL - United States TA - J Neurosci JT - The Journal of neuroscience : the official journal of the Society for Neuroscience JID - 8102140 RN - 0 (Calcium Channels, L-Type) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 9004-61-9 (Hyaluronic Acid) RN - EC 3.2.1.35 (Hyaluronoglucosaminidase) RN - EC 3.4.- (Metalloproteases) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - EC 3.4.24.17 (Mmp3 protein, mouse) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) RN - EC 3.4.24.35 (Mmp9 protein, mouse) SB - IM MH - Animals MH - CA1 Region, Hippocampal/drug effects MH - CA3 Region, Hippocampal/drug effects MH - Calcium Channels, L-Type/*drug effects/physiology MH - Hippocampus/*drug effects MH - Hyaluronic Acid/pharmacology MH - Hyaluronoglucosaminidase/pharmacology MH - In Vitro Techniques MH - Long-Term Potentiation/*drug effects MH - Matrix Metalloproteinase 3/genetics/metabolism MH - Matrix Metalloproteinase 9/genetics/metabolism MH - Metalloproteases/genetics/*physiology MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mossy Fibers, Hippocampal/drug effects MH - Neuronal Plasticity/drug effects MH - Proteolysis MH - Receptors, N-Methyl-D-Aspartate/*drug effects/genetics/physiology PMC - PMC6596865 OTO - NOTNLM OT - L-type calcium channels OT - extracellular matrix OT - long-term potentiation OT - matrix metalloproteinase OT - proteolysis OT - synaptic plasticity EDAT- 2017/01/11 06:00 MHDA- 2017/07/25 06:00 PMCR- 2017/08/01 CRDT- 2017/01/11 06:00 PHST- 2016/07/07 00:00 [received] PHST- 2016/10/21 00:00 [revised] PHST- 2016/11/12 00:00 [accepted] PHST- 2017/01/11 06:00 [pubmed] PHST- 2017/07/25 06:00 [medline] PHST- 2017/01/11 06:00 [entrez] PHST- 2017/08/01 00:00 [pmc-release] AID - JNEUROSCI.2170-16.2016 [pii] AID - 2170-16 [pii] AID - 10.1523/JNEUROSCI.2170-16.2016 [doi] PST - ppublish SO - J Neurosci. 2017 Feb 1;37(5):1240-1256. doi: 10.1523/JNEUROSCI.2170-16.2016. Epub 2017 Jan 9.