Important role of matrix metalloproteinase 9 in epileptogenesis |
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Authors: | Wilczynski Grzegorz M Konopacki Filip A Wilczek Ewa Lasiecka Zofia Gorlewicz Adam Michaluk Piotr Wawrzyniak Marcin Malinowska Monika Okulski Pawel Kolodziej Lukasz R Konopka Witold Duniec Kamila Mioduszewska Barbara Nikolaev Evgeni Walczak Agnieszka Owczarek Dorota Gorecki Dariusz C Zuschratter Werner Ottersen Ole Petter Kaczmarek Leszek |
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Institution: | Department of Neurophysiology, Nencki Institute, 02-093 Warsaw, Poland. G.Wilczynski@nencki.gov.pl |
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Abstract: | Temporal lobe epilepsy (TLE) is a devastating disease in which aberrant synaptic plasticity plays a major role. We identify matrix metalloproteinase (MMP) 9 as a novel synaptic enzyme and a key pathogenic factor in two animal models of TLE: kainate-evoked epilepsy and pentylenetetrazole (PTZ) kindling-induced epilepsy. Notably, we show that the sensitivity to PTZ epileptogenesis is decreased in MMP-9 knockout mice but is increased in a novel line of transgenic rats overexpressing MMP-9. Immunoelectron microscopy reveals that MMP-9 associates with hippocampal dendritic spines bearing asymmetrical (excitatory) synapses, where both the MMP-9 protein levels and enzymatic activity become strongly increased upon seizures. Further, we find that MMP-9 deficiency diminishes seizure-evoked pruning of dendritic spines and decreases aberrant synaptogenesis after mossy fiber sprouting. The latter observation provides a possible mechanistic basis for the effect of MMP-9 on epileptogenesis. Our work suggests that a synaptic pool of MMP-9 is critical for the sequence of events that underlie the development of seizures in animal models of TLE. |
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