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1

Impact of matrix metalloprotease inhibitor NNGH on long-term plasticity of NMDARs-mediated EPSPs in mouse CA1 hippocampal region

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Wojtowicz T., Brzdak P., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
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2014
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tom 74
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nr 3
The matrix metalloproteinases (MMPs) play a key role in synaptic plasticity, learning and memory. However, the underlying mechanisms remain poorly understood. Here we studied the role of MMPs inhibitor NNGH (10 µM) in shaping NMDAR-mediated component of synaptic plasticity by recording field potentials in Sch-CA1 hippocampal synapses in mice (P30-P45) brain slices. NMDAR-mediated EPSPs were isolated with AMPA/kainate receptors antagonist DNQX (20 µM) in Mg2+-free solutions. We found that NNGH completely abolished NMDAR-mediated LTP (178.7±12% vs. 75.8±2.9% of baseline at 1 hour post 4×100 Hz stimulation, n=6, P<0.05). The role of specific MMPs in this process is currently investigated. In conclusion, MMPs regulate NMDAR-mediated LTP and most likely postsynaptic calcium influx during long-term neuronal plasticity. Support: Ministry of Science and Higher Education grant NN401541540.
2

Synaptic plasticity at basal and apical dendrites of hippocampal neurons engage unique intracellular cascades and matrix metalloproteases subtypes

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Wojtowicz T., Brzdak P., Wojcicka O., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
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nr Suppl.1
Cognitive processes such as learning and memory require functional modifications within neural circuits which involve reorganization of existing synaptic connections and modulation of its strength. In addition, neurons can significantly enhance information storage capacity by scaling dendritic and somatic excitability (e.g. EPSP-to-spike potentiation). Proteolysis of extracellular matrix constituents and membrane proteins by matrix metalloproteases (MMP) has recently emerged as a key element in these processes. We identified NMDARs as a target for MMP-3 but not MMP-2/9 immediately following LTP induction. We next applied confocal imaging for nuclear cFos protein in brain slices fixed immediately following electrophysiology studies and Ca2+ imaging for somatodendritic NMDAR-mediated Ca2+ waves. We concluded that long-term hippocampal E-S potentiation limited to stratum radiatum inputs required MMP-3 activity in a narrow time window following enhanced neuronal activity that promotes NMDAR-mediated postsynaptic Ca2+ entry and activation of downstream signaling cascades leading to immediate early genes transcription. Most recently we discovered that in striking contrast to apical dendrites, synaptic plasticity induced at basal dendrites was insensitive to a wide range of broad and subtype specific MMP inhibitors. Thus, stratum radiatum synapses required MMP-3, alpha 5-integrins or protease-activated receptor 1 (PAR-1) and PKC kinase activity for modulation of NMDARs function, unlike stratum oriens synapses. FINANCIAL SUPPORT: National Science Center grant no. SONATA/2014/13/D/NZ4/03045.
3

Matrix metalloproteinase 3 critically affects postsynaptic long-term potentiation at GABAergic synapses in the mouse hippocampal CA1 region

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Brzdak P., Lebida K., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
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2019
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tom 79
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nr Suppl.1
INTRODUCTION: Matrix metalloproteinases (MMPs) are extracellular proteases that play a crucial role in various forms of neuronal plasticity. We have recently shown that MMP-3 supports NMDAR-mediated long-term potentiation and L-type calcium channel-dependent LTP. An extensive body of evidence revealed that, besides glutamatergic transmission, GABAergic synapses are also plastic; however, the underlying mechanisms remain elusive. AIM(S): Herein we addressed the question if activity of MMP-3 is involved in GABAergic synaptic plasticity in mice acute hippocampal slices. METHOD(S): We performed whole-cell patch-clamp recordings of miniature inhibitory postsynaptic currents (mIPSCs) from hippocampal CA1 pyramidal neurons. To induce iLTP, we applied NMDA in bath solution (3 min, 20µM) in the presence of 20 μM DNQX and 1μM TTX to slices from wild-type (WT) animals and mice lacking the mmp‑3 gene (MMP‑3 KO). To block the activity of MMP‑3, we used inhibitor UK 356618 (2 μM) in different time windows upon iLTP induction. RESULTS: We found that, in contrast to control conditions (WT), iLTP evoked in MMP-3 KO mice was completely abolished (CTR: 122±8%, n=9; MMP‑3 KO: 99±4%, n=13; p<0.05). We next studied the impact of the MMP‑3 inhibitor (UK356618) on iLTP during different time windows. The application of the MMP‑3 inhibitor before induction blocked iLTP (UK 356618: 92±3%; n=7; CTR: 116±3%; p<0.05). In slices that were treated with UK 356618 at various time points after starting the NMDA application, we found that the activity of MMP-3 is required for up to 13 minutes post induction of iLTP (UK 356618: 113±2%; n=6; CTR: 116±3%; n=7; p>0.05). CONCLUSIONS: The present results provide evidence that the activity of MMP-3 plays a crucial role in iLTP in the hippocampal CA1 region within a specific time window. FINANCIAL SUPPORT: Supported by Polish National Science Centre grant SONATA 2017/26/D/NZ4/00450 and PB is supported by Polish National Science Centre scholarship ETIUDA 2018/28/T/NZ4/00344.
4

GABAergic hippocampal plasticity critically depends on matrix metalloproteinase 3

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Mozrzymas J. W., Brzdak P., Lebida K., Lech A., Wiera G.
Acta Neurobiologiae Experimentalis
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2019
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tom 79
|
nr Suppl.1
Matrix metalloproteinases (MMPs) are known to play a crucialrole in neuronal plasticity. In particular, MMP‑3 has been reported to be involved in glutamatergic plasticity and related cognitive processes. Recently, a growing body of evidence indicates that GABAergic synapses are also plastic, but the underlying mechanisms remain elusive. Herein we addressed the question if the activity of MMP-3 is involved in GABAergic synaptic plasticity in mice acute hippocampal slices or in neuronal cultures. The presentation at symposium aims to offer an overview of experimental evidence obtained by our research group while more details will be presented at the posters. We performed whole‑cell patch‑clamp recordings of miniature inhibitory postsynaptic currents (mIPSCs) from hippocampal CA1 pyramidal neurons. To induce inhibitory LTP (iLTP), we applied NMDA in bath solution (3 min, 20µM) in the presence of 20 μM DNQX and 1μM TTX to slices or neuronal cultures from wild‑type (WT) animals and mice lacking mmp‑3 gene (MMP‑3 KO). To block the activity of MMP-3 we used inhibitor UK 356618 (2 μM). Besides functional manifestations, iLTP induction was associated with a significant increase in synaptic gephyrin cluster area. We found that, in both slices and neuronal cultures, iLTP evoked in MMP-3 KO mice was completely abolished in contrast to WT. An analogous effect was observed when using UK356618. Interestingly, administration of active MMP-3 to neuronal cultures resulted in iLTP and an increase in average size of synaptic gephyrin cluster. In addition, analysis of membrane mobility of synaptic GABAARs showed a decrease in their diffusion coefficient after MMP-3 treatment indicating a strengthening of inhibitory synapses through receptor trapping. We show that the activity of MMP-3 plays a crucial role in iLTP in the hippocampal CA1 region. FINANCIAL SUPPORT: Supported by Polish National Science Centre grant SONATA 2017/26/D/NZ4/00450 and PB is supported by Polish National Science Centre scholarship ETIUDA 2018/28/T/NZ4/00344.
5

Long-term gabaergic synaptic plasticity in hippocampus strongly depends on the activity of matrix metalloproteinase-3

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Brzdak P., Lebida K., Lech A., Nowak D., Wiera G., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
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2018
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tom 78
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nr Suppl.1
It is well established that matrix metalloproteinases (MMPs) play an important role in mechanisms of excit‑ atory plasticity, learning, and memory, especially those dependent on hippocampus. Recently, we have demon‑ strated that MMP-9, but not MMP-3, is involved in spike timing-dependent plasticity in mouse barrel cortex, and that MMP-3 supports NMDA-dependent LTP in the hip‑ pocampus. However, the contribution of these enzymes to GABAergic plasticity has not been investigated. To ad‑ dress this issue, we recorded miniature inhibitory post‑ synaptic currents (mIPSC) in acute hippocampal slices (P18-P21) and induced inhibitory LTP (iLTP) using NMDA treatment (3 min, 20 μM) in control conditions and in the presence of MMP inhibitors: FN-439 (180 µM), SB3‑CT (10 μM) and UK356618 (2 μM). Additionally, we performed immunostaining (against gephyrin and vGAT) of cultured hippocampal neurons and examined the level of MMP-3 using Western blot in hippocampal slice homogenates af‑ ter iLTP. We have shown that, in control conditions, ac‑ tivation of NMDA receptor significantly potentiated am‑ plitude (122±8%) and prolonged decay kinetics (125±7%) of mIPSC and also increased pro-MMP-3 levels (116±4%). Application of pan-MMP inhibitor (FN‑439) prevent‑ ed induction of iLTP (CTR: 122±8%, n=7; FN-439: 98±6%, n=7; p<0.05). Interestingly, MMP-3 inhibitor treatment (UK356618) blocked iLTP, but MMP‑9 inhibitor (SB3-CT) had no effect on iLTP (UK356618: 92±3%; n=7, p<0.05; SB3CT: 121±12%, n=6, p>0.05; in comparison to CTR: 122±8%, n=7). Thus, our data show that MMP‑3, but not gelatinases, supports iLTP. Moreover, in the hippocampal slices from mice lacking the Mmp-3 gene (MMP-3 KO) iLTP is also af‑ fected by MMP-3 deficiency (CTR: 122±6%, n=8; MMP-3 KO: 99±4%, n=13; p<0.05). Intriguingly, we ascertained that in this model the decay kinetics of mIPSCs were significant‑ ly slowed down with respect to control measurements (CTR: 14.81±0.61 ms, n=11; MMP-3 KO: 18.31±0.99 ms, n=12; p<0.05). Similarly, iLTP was impaired in the MMP-3 KO group in hippocampal neuronal cultures. In addition, we observed a significant increase in synaptic gephyrin clus‑ ter area after iLTP (120±3%), but not after UK356618 treat‑ ment (99±3%) in neuronal cultures. Taken together, these data reveal that GABAergic LTP depends on extracellular proteolysis mediated by MMP-3. Supported by Polish Na‑ tional Science Centre grant OPUS/2014/15/B/NZ4/01689 and OPUS/2013/11/B/NZ3/00983.
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