Maintenance of long‐term potentiation in hippocampal mossy fiber—CA3 pathway requires fine‐tuned MMP‐9 proteolytic activity

Mechanisms of synaptic plasticity involve proteolytic activity mediated by a complex system of proteases, including members of metalloproteinase (MMP) family. In particular, MMP‐9 is critical in LTP maintenance in the Schaffer collateral‐CA1 pathway and in the acquisition of hippocampus‐dependent memory. Recent studies from this laboratory revealed that in the mossy fiber‐CA3 (MF‐CA3) projection, where LTP induction and expression are largely presynaptic, MMPs blockade disrupts LTP maintenance and that LTP induction is associated with increased MMP‐9 expression. Here we used acute brain slices from MMP‐9 knock‐out mice and transgenic rats overexpressing MMP‐9 to determine how manipulations in endogenous MMP‐9 affect LTP in the MF‐CA3 projection. Both types of transgenic models showed a normal basal synaptic transmission and short‐term plasticity. Interestingly, the maintenance of LTP induced in slices from knock‐out mice and overexpressing rats was nearly abolished. However, in the presence of active MMP‐9, a gradual fEPSP autopotentiation was observed and tetanization evoked a marked LTP in knock‐out mice. Additionally, in MMP‐9‐treated slices from wild‐type mice, fEPSP autopotentiation also occurred and partially occluded LTP. This indicates that exogenous protease can restore LTP in null mice whereas in the wild‐type, MMP‐9 excess impairs LTP. We expected that LTP maintenance in transgenic rats could be re‐established by a partial MMP blockade but non‐saturating concentrations of MMP inhibitor were ineffective. In conclusion, we demonstrate that LTP maintenance in MF‐CA3 pathway requires fine‐tuned MMP‐9 activity and raises the possibility that altered MMP‐9 level might be detrimental for cognitive processes as observed in some neuropathologies. © 2013 Wiley Periodicals, Inc.

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