Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) Is Differentially Induced in Neurons and Astrocytes after Seizures: Evidence for Developmental, Immediate Early Gene, and Lesion Response

Abstract

We investigated in vivo the expression of the tissue inhibitor of metalloproteinases-1 (TIMP-1) in the rat CNS after kainate (KA)-induced excitotoxic seizures. In situ hybridization revealed that TIMP-1 mRNA is induced rapidly and massively in most regions of the adult forebrain after KA treatment. Neuronal activity seems to be necessary but not sufficient to trigger TIMP-1 induction, because it is not observed in seizing 10-d-old pups, unlike what is observed in 21-and 35-d-old animals after seizures. The rapid induction of TIMP-1 is not prevented by the inhibitor of protein synthesis cycloheximide, suggesting that, after seizures, TIMP-1 is induced in neurons as an immediate early gene (IEG). The initial neuronal upregulation is followed by enhanced expression in astrocytes, as assessed by double-labeling experiments. In the hippocampus rapid increases in mRNA are followed by relatively delayed (8 hr after KA) increases in TIMP-1 immunoreactivity in the perisomatic and dendro-axonic areas, suggesting secretion of the protein. At 3 d after KA treatment, strong immunoreactivity is found in astrocytes and in the cell bodies and dendro-axonic projections of resistant neurons such as the dentate granule cells. Taken together, the results suggest that TIMP-1 may be instrumental for neurons and astrocytes in coupling early cellular events triggered by seizures with the regulation of long-lasting changes involved in tissue reorganization and/or neuroprotection.

Matrix Metalloproteinase-9 Undergoes Expression and Activation during Dendritic Remodeling in Adult Hippocampus

“…Whereas the dendritic translocation of MMP-9 mRNA appears to be an especially plausible and attractive explanation for our result, one should also alternatively consider enhanced mRNA accumulation in local glia. However, we did not observe either punctate distribution of the MMP-9 within other parts of hippocampus or its upregulation in lesioned pyriform cortex, patterns that are typical for glia gene expression in neurodegeneration (Rivera et al, 1997).…”

“…Recently, it has been demonstrated that neuronal TIMP-1 is regulated by synaptic activity (Nedivi et al, 1993;Rivera et al, 1997;Jaworski et al, 1999). This prompted us to address the hypothesis that MMPs are involved in the activity-dependent reorganization of neuronal architecture.…”

Tissue inhibitor of metalloproteinases-3 (TIMP-3) expression is increased during serum deprivation-induced neuronal apoptosis in vitro and in the G93A mouse model of amyotrophic lateral sclerosis: A potential modulator of Fas-mediated apoptosis

“…Levels of TIMP-1 expression were found to be increased in the hippocampal formation after transient forebrain ischemia or seizure and in the retinal ganglion cell layer after elevation of intraocular pressure (Rivera et al, 1997(Rivera et al, , 2002Jourquin et al, 2005). Manipulations increasing TIMP-1 were shown to protect neurons in dissociated and organotypic hippocampal cultures from excitotoxicity but not from apoptosis induced by withdrawal of nerve growth factor or chemical-induced ischemia (Tan et al, 2003).…”

Le système MMP/TIMP dans le système nerveux

“…Chez le rat, l'expression de TIMP-1 est fortement augmentée dans les neurones des grains de l'hippocampe quelques minutes après la reperfusion isché-mique ou le déclenchement de crises convulsives. Quelques jours plus tard, la synthèse de TIMP-1 est induite dans des astrocytes réactifs proches des neurones lésés, mais pas dans la microglie réactive [8,9]. Il a également été décrit une augmentation des concentrations de MMP-9 et -2 après une crise d'épi-lepsie ou une ischémie cérébrale chez le rat [9- adapté les techniques de zymographie in situ pour étudier dans le système nerveux, et avec une résolution cellulaire, les modulations de l'activité des MMP au cours de diffé-rents processus pathologiques.…”