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-3inthisformofLTP.IncontrasttotheCA3-CA1pathway,LTPinthemossyfiber-CA3projectiondidnotdependonMMP-3,indicatingthe pathway specificity of the actions of MMPs. Overall, our study indicates that the activation of perisynaptic MMP-3 supports L-type channeldependent LTP in the CA1 region, whereas nmdaLTP depends solely on MMP-9.

The extracellular matrix (ECM) and membrane proteolysis play a key role in structural and functional synaptic plasticity associated with development and learning. A growing body of evidence underscores the multifaceted role of members of the metzincin superfamily, including metalloproteinases (MMPs), A Disintegrin and Metalloproteinases (ADAMs), A Disintegrin and Metalloproteinase with Thrombospondin Motifs (ADAMTSs) and astacins in physiological and pathological processes in the central nervous system (CNS). The expression and activity of metzincins are strictly controlled at different levels (e.g., through the regulation of translation, limited activation in the extracellular space, the binding of endogenous inhibitors and interactions with other proteins). Thus, unsurprising is that the dysregulation of proteolytic activity, especially the greater expression and activation of metzincins, is associated with neurodegenerative disorders that are considered synaptopathies, especially Alzheimer’s disease (AD). We review current knowledge of the functions of metzincins in the development of AD, mainly the proteolytic processing of amyloid precursor protein, the degradation of amyloid β (Aβ) peptide and several pathways for Aβ clearance across brain barriers (i.e., blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB)) that contain specific receptors that mediate the uptake of Aβ peptide. Controlling the proteolytic activity of metzincins in Aβ-induced pathological changes in AD patients’ brains may be a promising therapeutic strategy.

Over the past two decades, metalloproteinases (MMPs), including MMP-2, MMP-3, and MMP-9, have been implicated as important players in mechanisms underlying various forms of neuroplasticity. In particular, MMP-3 was found to be involved in both cognitive functions and in plasticity phenomena, but the underlying molecular mechanisms remain largely elusive. In general, it is believed that functional plasticity of neurons is associated with morphological alterations. Interestingly, MMP-9, in addition to playing a key role in synaptic plasticity, was found to affect plasticity-related spine morphology changes. Whereas the involvement of MMP-3 in shaping synapse morphology upon induction of synaptic plasticity awaits determination, it has been demostrated that MMP-3 knockout results in clearly altered apical dendrite morphology in pyramidal neurons in mouse visual cortex. Considering that the involvement of MMP-3 in synaptic plasticity has been most extensively documented for the CA1 hippocampal region, we decided to investigate whether genetic deletion of MMP-3 affects neuronal morphology in this area. To this end, we used Golgi staining to compare dendritic morphology of pyramidal neurons in the CA1 region in MMP-3-deficient and wild-type mice. Surprisingly, in contrast to the results obtained in cortex, extensive analysis of dendritic morphology in the CA1 region revealed no significant differences between MMP-3 knockout and wild-type groups. These results suggest that the impact of MMP-3 on neuronal morphology may be region-specific.

No abstract