Long-term potentiation (LTP) is widely perceived as a memory substrate and in the hippocampal CA3-CA1 pathway, distinct forms of LTP depend on N-methyl-D-aspartate (NMDA) receptors (nmdaLTP) or L-type voltage-gated calcium channels (vdccLTP). Long-term potentiation 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 knockout 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 knockout 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.
The authors declare that they have no conflict of interest.
We thank Leszek Kaczmarek from Nencki Institute in Warsaw for providing us MMP-9 KO mice. This work was supported by Polish National Science Centre grants: 2013/08/T/NZ3/00999 (scholarship for G.W.) and 2014/15/B/NZ4/01689 (J.W.M.). This work was partially supported by the KU Leuven Research Council (KU Leuven, Belgium, BOF-OT/14/064, to L.M.), the Research Foundation Flanders (Belgium, FWO G.0054.12, G0B2315N, to L.M.) and the Flemish government agency for Innovation by Science and Technology (Belgium, post-doc fellowship I.V.H.). G.W. was additionally supported by Stipend for Young Researchers START from Foundation for Polish Science.