Important role of matrix metalloproteinase 9 in epileptogenesis

G. Wilczynski, F. Konopacki, E. Wilczek, Z. Lasiecka, A. Gorlewicz, P. Michaluk, M. Wawrzyniak, M. Malinowska, P. Okulski, L. Kolodziej, W. Konopka, K. Duniec, B. Mioduszewska, E. Nikolaev, A. Walczak, D. Owczarek, Darek Gorecki, W. Zuschratter, O. Ottersen, L. Kaczmarek

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)1021-1035
Number of pages15
JournalJournal of Cell Biology
Volume180
Issue number5
DOIs
Publication statusPublished - 2008

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