Long-term plasticity of inhibitory synapses in the hippocampus and spatial learning depends on matrix metalloproteinase
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Cellular and Molecular Life Sciences
ORIGINAL ARTICLE
Long‑term plasticity of inhibitory synapses in the hippocampus and spatial learning depends on matrix metalloproteinase 3 Grzegorz Wiera1 · Katarzyna Lebida1 · Anna Maria Lech1,2 · Patrycja Brzdąk1,2 · Inge Van Hove3 · Lies De Groef3,4 · Lieve Moons3,4 · Enrica Maria Petrini5 · Andrea Barberis5 · Jerzy W. Mozrzymas1 Received: 27 April 2020 / Revised: 19 August 2020 / Accepted: 3 September 2020 © The Author(s) 2020
Abstract Learning and memory are known to depend on synaptic plasticity. Whereas the involvement of plastic changes at excitatory synapses is well established, plasticity mechanisms at inhibitory synapses only start to be discovered. Extracellular proteolysis is known to be a key factor in glutamatergic plasticity but nothing is known about its role at GABAergic synapses. We reveal that pharmacological inhibition of MMP3 activity or genetic knockout of the Mmp3 gene abolishes induction of postsynaptic iLTP. Moreover, the application of exogenous active MMP3 mimics major iLTP manifestations: increased mIPSCs amplitude, enlargement of synaptic gephyrin clusters, and a decrease in the diffusion coefficient of synaptic GABAA receptors that favors their entrapment within the synapse. Finally, we found that MMP3 deficient mice show faster spatial learning in Morris water maze and enhanced contextual fear conditioning. We conclude that MMP3 plays a key role in iLTP mechanisms and in the behaviors that presumably in part depend on GABAergic plasticity. Keywords GABA · iLTP · Mmps · Metalloproteinases · Synaptic plasticity · Synaptic inhibition
Introduction
Grzegorz Wiera and Katarzyna Lebida equal contribution. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00018-020-03640-6) contains supplementary material, which is available to authorized users. * Grzegorz Wiera [email protected] * Katarzyna Lebida [email protected] 1
Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, 50‑367, Wroclaw, Poland
2
Laboratory of Cellular Neurobiology, Department of Physiology and Molecular Neurobiology, Wroclaw University, 50‑205, Wroclaw, Poland
3
Neural Circuit Development and Regeneration Research Group, Department of Biology, University of Leuven (KU Leuven), 3000 Leuven, Belgium
4
Leuven Brain Institute (LBI), KU Leuven, Leuven, Belgium
5
Laboratory of Synaptic Plasticity of Inhibitory Networks, Fondazione Istituto Italiano Di Tecnologia, 16163 Genoa, Italy
Learning and memory formation have been primarily associated with the plasticity of excitatory glutamatergic synapses [1], the mechanisms of which have been studied for more than four decades [2, 3]. More recently, however, inhibitory GABAergic synapses were found to exhibit many forms of long-term plasticity that is putatively important in learning and memory [4, 5]. At the circuit level, plastic changes at GABAergic synapses are thought to regulate numerous phenomena, such as the pl
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