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1

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
|
2019
|
tom 79
|
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.
2

Synaptic plasticity in barrel cortex is occluded by classical conditioning training and depends on the activity of metalloproteinases

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Lebida K., Urban-Ciecko J., Mozrzymas J.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr S
It is well established that classical conditioning paradigms induce plastic changes in the mouse barrel cortex. In particular, tactile whisker stimulation paired with a tail shock affects GABAergic currents in the layer IV in the cell-specific manner. It is thus expected that sensory learning might affect the neuronal networks in the “trained” barrel, possibly altering its ability to express the synaptic plasticity. To test this possibility, we have compared the long-term potentiation (LTP) induction in “trained” barrels in slices from animals which underwent classical conditioning to that in corresponding barrels in control (yoked, pseudoconditioned) mice. To induce LTP, classical pairing protocol was used (stimulation - layer IV, current-clamp whole-cell recordings - layer II/III). Interestingly, while in control mice, pairing resulted in a clear LTP (161% EPSP increase, 30 min after pairing), in trained animals the LTP induction was nearly absent. This result suggests that behavioral learning occludes the synaptic plasticity in the considered model. It has been demonstrated in other brain region (hippocampus) that synaptic plasticity as well as behavioural learning may critically depend on the activity of metalloproteases (MMPs). We were thus interested whether LTP in the barrel cortex depends on these enzymes. To address this issue, pairing protocol was used to induce LTP in the barrel cortex of control animals and MMPs were blocked by a broad spectrum MMP inhibitor (FN-439). We found that pre-treatment of slices with MMPs inhibitor practically abolished LTP indicating that these enzymes play a critical role in the LTP maintenance in this model. In conclusion, these data indicate that behavioural learning occludes the synaptic plasticity in the barrel cortex and that LTP maintenance in this preparation relies on the activity of MMPs. Supported by the Ministry of Science and Higher Education grants N401 028 32/0664 and NN401541540.
3

GABAergic hippocampal plasticity critically depends on matrix metalloproteinase 3

88%
Mozrzymas J. W., Brzdak P., Lebida K., Lech A., Wiera G.
Acta Neurobiologiae Experimentalis
|
2019
|
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.
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Impact of matrix metalloproteinase-9 overexpression on synaptic excitatory transmission and its plasticity in rat Ca3-Ca1 hippocampal pathway

76%
Wiera G., Szczot M., Wojtowicz T., Lebida K., Koza P., Mozrzymas J. W.
Journal of Physiology and Pharmacology
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2015
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tom 66
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nr 2
5

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

76%
Brzdak P., Lebida K., Lech A., Nowak D., Wiera G., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2018
|
tom 78
|
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.
6

Induction of long term potentiation in DG-CA3 hippocampal pathway results in increased MMP-2/9 gelatinolysis in target hilar and CA3 neurons

64%
Wojtowicz T., Gendosz D., Lebida K., Drulis-Fajdasz D., Wiera G., Caponga M., Wilczynski G., Dziegiel P., Mozrzymas J. W.
Acta Neurobiologiae Experimentalis
|
2011
|
tom 71
|
nr S
Matrix metalloproteinases (MMPs) are capable of remodeling extracellular matrix and have been implicated in synaptic plasticity, learning and memory. In particular, upregulation of gelatinases (MMP-2 and 9) accompanies long-term potentiation (LTP) in hippocampal Schaeffer collateral-CA1 pathway. However, the role of gelatinases in synaptic plasticity in other hippocampal pathways remains unknown. Recently, we have found that MMPs blockade by FN-439 abolishes LTP consolidation in the dentate gyrus-CA3 (DG-CA3) projection (where LTP expression is presynaptic, Wójtowicz and Mozrzymas 2010). To address the involvement of gelatinases in the plasticity of this pathway, we have combined high resolution in situ zymography with DQ-gelatin (DQ-G) and immunofluorescence in hippocampal sections from slices used in electrophysiological experiments. LTP was evoked by high frequency stimulation (HFS, 4×100 Hz) while baseline (control) stimulation was applied at 0.1 Hz. Following fixation, slices were cut into thin sections, treated with DQ-G and stained against a neuronal marker MAP-2. The intensity of DQ-G fluorescence was quantified for MAP-2 positive neurons using confocal microscopy. Computer- and visually-guided analysis of cytoplasm and proximal dendrites of target hilar and CA3 neurons revealed that LTP induction was associated with a significant increase in DQ-G fluorescence (30% and 35% increase, respectively, n=6 animals, p<0.05). Importantly, cytoplasmic DQ-G fluorescence profile corroborated with immunoreactivity for MMP-9. The overall DQ-G fluorescence signal in MAP-2 and GFAP-negative extracellular space did not differ between control and HFS-stimulated preparations (n=6 animals, p=0.89). In conclusion, we provide evidence that stimulation pattern that evokes LTP in the DG-CA3 pathway, induces a significant up regulation of gelatinases in the cytoplasm of postsynaptic hilar and CA3 neurons. Support: Grants NN401541540 and UDA-POKL.04.01.01-00-010/08-01.
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