Alterations in cyclin A, B, and D1 in mouse dentate gyrus following TMT-induced hippocampal damage.
The interactions of glia and neurons during injury and subsequent neurodegeneration are a subject of interest both in disease and chemical-induced brain injury. One such model is the prototypical hippocampal toxicant trimethyltin (TMT). An acute injection of TMT (2.0 mg/kg, i.p.) to postnatal day 21 CD-1 male mice produced neuronal necrosis and loss of dentate granule cells, astrocyte hypertrophy, and microglia activation in the hippocampus within 24 hrs. Neuronal necrosis and microglia differentiation to a phagocytic phenotype is temporally correlated with peak elevations in TNF-alpha, cyclin A2, cyclin B1 and cyclin D1 at 72 h post-TMT. TNF-alpha mRNA levels were significantly elevated in the hippocampus by 12 h and remained elevated for 72 h. mRNA levels for cyclin A2 and cyclin B1 were elevated by approximately 2-fold at 72 h. Immunohistochemistry suggested a cellular localization of cyclin A to microglia in the region of neuronal necrosis in the dentate, cyclin B in glial cells in juxtaposition to neurons in the hilus of the hippocampus and cyclin D1 to non-glial cells in the dentate. mRNA levels for cyclin D1 were elevated approximately 1.5-fold by 72 h as determined by RNase protection assay. No changes were seen in mRNA levels for cyclins E, F, G1, G2, H or I nor cyclin dependent kinases. These elevations are not associated with proliferation of microglia as determined by BrdU incorporation and Ki-67 immunohistochemistry. Upregulation of cell cycle genes was associated with cellular processes other than proliferation and may contribute to the differentiation of microglia to a phagocytic phenotype. These data suggest an integrated role for cell cycle regulation of neural cells in the manifestation of hippocampal pathophysiology.
McPherson
Christopher A
CA
Neurotoxicology Group, National Institute of Environmental Health Sciences,Research Triangle Park, NC 27709, USA.
Kubik
Julie
J
Wine
Robert N
RN
D'Hellencourt
Christian Lefebvre
CL
Harry
G Jean
GJ
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D019925:Cyclin A / Q000096:biosynthesis / Q000378:metabolism*; D019926:Cyclin B / Q000096:biosynthesis / Q000378:metabolism*; D019938:Cyclin D1 / Q000096:biosynthesis / Q000378:metabolism*; D018891:Dentate Gyrus / Q000187:drug effects / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D023282:Nuclease Protection Assays; D012333:RNA, Messenger / Q000096:biosynthesis; D014298:Trimethyltin Compounds / Q000633:toxicity*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D019925:Cyclin A; D019926:Cyclin B; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014298:Trimethyltin Compounds; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; C046488:trimethyltin