Important role of matrix metalloproteinase 9 in epileptogenesis

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.

Metalloproteinase-9 contributes to inflammatory glia activation and nigro-striatal pathway degeneration in both mouse and monkey models of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism

“…Qualitative and quantitative data, obtained by co-immunolabeling MMP-9 with different cell-specific markers, show significant enhancement of MMP-9 expression in reactive microglia and astrocytes recruited in SNpc and striatum. This is in accord to the literature, where it is reported that neurons, microglia and astrocytes synthesize both gelatinases (MMP-2 and MMP-9), although MMP-9 is the only highly modulated under experimental conditions (Yong 2005;Wilczynski et al 2008;Candelario-Jalil et al 2009;Walker and Rosenberg 2010). In MPTP-injected mice, neuroinflammation is transient and starts decreasing within 2 weeks after the treatment, when the number of MMP-9 ?…”

Neuronal Per Arnt Sim (PAS) Domain Protein 4 (NPAS4) Regulates Neurite Outgrowth and Phosphorylation of Synapsin I

“…It is therefore likely that unidentified downstream signaling mechanisms other than CDK5 of NPAS4 may operate in the regulation of SYN I phosphorylation in neurons. To address this issue, further experiments with other animal models of epileptogenesis (42) are necessary in Npas4 KO mice.…”

Matrix Metalloproteinase-9 Contributes to Kindled Seizure Development in Pentylenetetrazole-Treated Mice by Converting Pro-BDNF to Mature BDNF in the Hippocampus

“…Recent studies have linked MMPs to various pathologic conditions in the central nervous system, including ischemia, multiple sclerosis, Parkinson's disease, malignant glioma, Alzheimer's disease, and epilepsy. Interestingly, some evidence suggests that, in addition to its known extracellular role in macromolecule degradation, MMP may mediate apoptotic and/or necrotic cell death (Jourquin et al, 2003;Kim et al, 2009) and synaptic plasticity (Tian et al, 2007;Wilczynski et al, 2008;Takács et al, 2010). The gelatinases MMP-2 and MMP-9 are initially expressed as inactive proenzymes that are cleaved to their active forms after they are released from cells (Van den Steen et al, 2002), allowing these proteases to regulate the levels of extracellular substrates.…”

“…Jourquin et al (2003) used organotypic cultures to demonstrate increased release and activity of MMP-9 after stimulation with neurotoxic kainate and reduced neuronal cell death following MMP-9 inhibition. Although MMP-9 is expressed in response to neural activity in some models of epileptogenesis (Wilczynski et al, 2008;Kim et al, 2009;Takács et al, 2010), the pathophysiologic and etiologic roles of this metalloproteinase, including potential molecular targets, during kindling seizure development have not been elucidated. In the present study, we used MMP-9 homozygous knock-out (Ϫ/Ϫ) )mice to investigate the role of MMP-9 in kindling induced by pentylenetetrazole (PTZ).…”