INTRODUCTION: Formation of memory traces, and thus learning, strongly relies on the interplay between different forms of neuronal plasticity. While much is known about the plasticity of glutamatergic synapses, plasticity of synaptic inhibition awaits deeper investigations. AIM(S): The aim of this study was to address the function of extracellular proteolysis mediated by matrix metalloprotease‑3 (MMP‑3) in GABAergic plasticity. METHOD(S): We recorded mIPSCs in hippocampal culture and induced inhibitory LTP (iLTP) using NMDA in the presence of MMP‑3 inhibitor UK‑356618. Additionally, we studied changes in morphology of GABAergic synapses and membrane lateral mobility of GABAARs. RESULTS: Obtained results clearly show that, in the presence of UK or in MMP-3 deficient neurons, iLTP is abolished (WT: 116%; UK: 96%, n=8‑9, p=0.02). Concurrently, we observed a significant increase in synaptic gephyrin cluster area after iLTP induction in controls (WT: 121%, n=23) but not in the presence of UK (98%, n=25, p<0.01). We also investigated the effects of exogenous active MMP-3 on synaptic morphology, membrane mobility of GABAA receptors, and the amplitude of mIPSC. Short‑term MMP‑3 application augments mIPSC amplitude up to 121% of initial value (n=11, p<0.01) and increases the average size of synaptic gephyrin cluster (108%, n=16, p<0.05). In addition, analysis of membrane mobility of synaptic GABAARs showed a decrease in their diffusion coefficient after MMP-3 treatment (before: 0.019µm2 /s; after MMP‑3: 0.015µm2 /s, p<0.01) indicating the strengthening of inhibitory synapses through receptor trapping. CONCLUSIONS: These results demonstrate a crucial role of MMP-3 in the induction of iLTP both at functional and morphological level opening new avenues in the study of plasticity cross-talk between different synapses. Additionally, presented results significantly expand our knowledge on the local interplay between extracellular matrix and inhibitory synapses. FINANCIAL SUPPORT: NCN grant 2017/26/D/ NZ4/00450.
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