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.
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.
Rivera
S
S
Université René Descartes, Paris V, Institut National de la Santé et de la Recherche Médicale Unité-29, 75014 Paris, France.
Tremblay
E
E
Timsit
S
S
Canals
O
O
Ben-Ari
Y
Y
Khrestchatisky
M
M
D000367:Age Factors; D000818:Animals; D000918:Antibody Specificity; D001253:Astrocytes / Q000737:chemistry / Q000378:metabolism*; D015415:Biomarkers; D016923:Cell Death / Q000235:genetics; D003513:Cycloheximide / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005109:Extracellular Matrix / Q000201:enzymology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D017781:Genes, Immediate-Early / Q000502:physiology; D006023:Glycoproteins / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D006624:Hippocampus / Q000737:chemistry / Q000166:cytology / Q000503:physiopathology; D006801:Humans; D007608:Kainic Acid / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D011480:Protease Inhibitors / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000235:genetics*; D019714:Tissue Inhibitor of Metalloproteinases
D015415:Biomarkers; D018690:Excitatory Amino Acid Agonists; D006023:Glycoproteins; D011480:Protease Inhibitors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D003513:Cycloheximide; D007608:Kainic Acid