Published online
doi:10.1083/jcb.200708213
The Journal of Cell Biology, Vol. 180, No. 5, 1021-1035
The Rockefeller University Press, 0021-9525 $30.00
© Wilczynski et al.
Important role of matrix metalloproteinase 9 in epileptogenesis
Grzegorz M. Wilczynski1,3,
Filip A. Konopacki1,2,5,
Ewa Wilczek4,
Zofia Lasiecka1,
Adam Gorlewicz1,
Piotr Michaluk2,
Marcin Wawrzyniak2,
Monika Malinowska1,
Pawel Okulski2,
Lukasz R. Kolodziej2,
Witold Konopka2,
Kamila Duniec2,5,
Barbara Mioduszewska2,
Evgeni Nikolaev2,
Agnieszka Walczak1,
Dorota Owczarek1,
Dariusz C. Gorecki6,
Werner Zuschratter7,
Ole Petter Ottersen8, and
Leszek Kaczmarek2
1 Department of Neurophysiology and 2 Department of Molecular and Cellular Neurobiology, Nencki Institute, 02-093 Warsaw, Poland
3 Department of Histology and Embryology and 4 Department of Pathology, Medical University of Warsaw, 02-005 Warsaw, Poland
5 Postgraduate School of Molecular Medicine, 02-093 Warsaw, Poland
6 Institute of Biomedical and Biomolecular Sciences, University of Portsmouth, PO1 2DT Portsmouth, England, UK
7 Leibniz Institute for Neurobiology, D-39118 Magdeburg, Germany
8 Centre for Molecular Biology and Neuroscience, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway
Correspondence to Leszek Kaczmarek: L.Kaczmarek{at}nencki.gov.pl; or Grzegorz M. Wilczynski: G.Wilczynski{at}nencki.gov.pl
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.
Abbreviations used in this paper: ANOVA, analysis of variance; DG, dentate gyrus; DIV, day in vitro; GFAP, glial fibrillary acidic protein; ICAM, intercellular adhesion molecule; IR, immunoreactivity; KA, kainic acid; KO, knockout; MMP, matrix metalloproteinase; NMDAR, N-methyl D-aspartate acid receptor; PSD, postsynaptic density; PTZ, pentylenetetrazole; TG, transgenic; TLE, temporal lobe epilepsy; tPA, tissue plasminogen activator; WT, wild type.
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