Important role of matrix metalloproteinase 9 in epileptogenesis.
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.
Wilczynski
Grzegorz M
GM
Department of Neurophysiology, Nencki Institute, 02-093 Warsaw, Poland. G.Wilczynski@nencki.gov.pl
Konopacki
Filip A
FA
Wilczek
Ewa
E
Lasiecka
Zofia
Z
Gorlewicz
Adam
A
Michaluk
Piotr
P
Wawrzyniak
Marcin
M
Malinowska
Monika
M
Okulski
Pawel
P
Kolodziej
Lukasz R
LR
Konopka
Witold
W
Duniec
Kamila
K
Mioduszewska
Barbara
B
Nikolaev
Evgeni
E
Walczak
Agnieszka
A
Owczarek
Dorota
D
Gorecki
Dariusz C
DC
Zuschratter
Werner
W
Ottersen
Ole Petter
OP
Kaczmarek
Leszek
L
D000818:Animals; D030801:Animals, Genetically Modified; D003292:Convulsants; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004827:Epilepsy / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology; D006624:Hippocampus / Q000002:abnormalities* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D019599:Mossy Fibers, Hippocampal / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology; D009434:Neural Pathways / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000235:genetics; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000378:metabolism* / Q000473:pathology
D003292:Convulsants; D020780:Matrix Metalloproteinase 9