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-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.

Disruption of perineuronal nets increases the frequency of sharp wave ripple events

“…Glial cells express critical components of the PNN, and expression of components is regulated by factors including neuronal activity (Howell and Gottschall, ; Matthews et al, ; McRae et al, ; Song and Dityatev, ). In addition, several PNN cleaving enzymes are expressed by neurons and glia (Brzdak, Wlodarczyk, Mozrzymas, & Wojtowicz, ; Deb and Gottschall, ; Dubey et al, ; Janusz et al, ; Pollock, Everest, Brown, & Poulter, ; Szklarczyk, Lapinska, Rylski, McKay, & Kaczmarek, ; Wiera et al, ; Yong, Krekoski, Forsyth, Bell, & Edwards, ). Soluble and transmembrane matrix metalloproteinases have been particularly well studied for their potential to disrupt PNN integrity, and their expression and/or activity is can be dramatically altered by physiological or pathological neuronal activity (Conant et al, ; Meighan et al, ; Nagy et al, ), disease states and select therapeutics (Pollock et al, ; Szklarczyk et al, ).…”

Disruption of perineuronal nets increases the frequency of sharp wave ripples

“…Glial cells express critical components of the PNN, and expression of components is regulated by factors including neuronal activity (Howell and Gottschall, 2012;Matthews et al, 2002;McRae et al, 2007;Song and Dityatev, 2017). In addition, several PNN cleaving enzymes are expressed by neurons and glia (Brzdak et al, 2017;Deb and Gottschall, 1996;Dubey et al, 2017;Janusz et al, 2013;Pollock et al, 2014;Szklarczyk et al, 2002;Wiera et al, 2017;Yong et al, 1998). Soluble and transmembrane matrix metalloproteinases have been particularly well studied for their potential to disrupt PNN integrity, and their expression and/or activity is can be dramatically altered by physiological or pathological neuronal activity (Conant et al, 2010;Meighan et al, 2006;Nagy et al, 2006), disease states and select therapeutics (Szklarczyk et al, 2002).…”

Matrix metalloproteinase-3 in brain physiology and neurodegeneration

“…25,26 Thus, not surprisingly, MMPs are precisely controlled. In the CNS, MMPs are expressed and secreted both by neurons and glial cells 13 but their activity in normal conditions is low. The level of MMP activity significantly increases only in specific time windows, for example, during the induction of synaptic plasticity or repairing processes.…”

“…Moreover, recent studies have confirmed that MMP-3 activity is indeed crucial in regulating vdcc-dependent form of LTP in hippocampus, but not for nmdaLTP (that is regulated, e.g., by MMP-9). 13 Nevertheless, there is also some evidence that MMP-3 can affect NMDA receptors. In cultured spinal cord neurons, chronic NMDAR overstimulation leads to an increase in MMP-3 activity which, in turn, cleaves GluN1 subunit of NMDA receptor to constrain calcium influx and prevent neuron apoptosis.…”

“…In recent years, numerous studies described the crucial role played by MMPs-dependent ECM proteolysis in physiological processes such as synaptic plasticity, learning and memory. 12,13 Nonetheless, abnormal expression, localization and activity of MMPs could have a detrimental impact on brain functioning, 6,14,15 and, in physiological conditions, MMPs activity is kept under strict control at both the transcriptional and cellular levels by controlling the synthesis, release, activation, inhibition, and degradation.…”