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

• Autorzy: Brzdak P. , Lebida K. , Lech A. , Nowak D. , Wiera G. , Mozrzymas J.W.
• Języki publikacji: EN

Abstrakty

EN

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.

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2018
• Tom: 78
• Numer: Suppl.1
• Opis fizyczny: p.13-14

Twórcy

autor

Brzdak P.

• Laboratory of Neuroscience, Department Biophysics, Wroclaw Medical University, Wroclaw, Poland
• Department of Physiology and Molecular Neurobiology, Wroclaw University, Wroclaw, Poland

autor

Lebida K.

• Laboratory of Neuroscience, Department Biophysics, Wroclaw Medical University, Wroclaw, Poland

autor

Lech A.

• Department of Physiology and Molecular Neurobiology, Wroclaw University, Wroclaw, Poland

autor

Nowak D.

• Laboratory of Neuroscience, Department Biophysics, Wroclaw Medical University, Wroclaw, Poland
• Department of Physiology and Molecular Neurobiology, Wroclaw University, Wroclaw, Poland

autor

Wiera G.

• Laboratory of Neuroscience, Department Biophysics, Wroclaw Medical University, Wroclaw, Poland
• Department of Physiology and Molecular Neurobiology, Wroclaw University, Wroclaw, Poland

autor

Mozrzymas J.W.

• Laboratory of Neuroscience, Department Biophysics, Wroclaw Medical University, Wroclaw, Poland
• Department of Physiology and Molecular Neurobiology, Wroclaw University, Wroclaw, Poland