Alterations in cyclin A, B, and D1 in mouse dentate gyrus following TMT-induced hippocampal damage

Abstract

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.

Trimethyltin-induced neurogenesis in the murine hippocampus

“…This proliferative response occurred during the active process of neuronal degeneration, microglia phagocytosis of neuronal debri, and under highly inflammatory conditions. These findings are in agreement with the previously reported observation of an activation of cell cycle pathways in both glia and newly generated neurons following TMT (McPherson et al, 2003). It is known that during development, post-mitotic neurons generated from precursor cells continue to express cell cycle components for a short time period after terminal differentiation (Freeman et al, 1994;Padmanabhan et al, 1999).…”

“…It is known that during development, post-mitotic neurons generated from precursor cells continue to express cell cycle components for a short time period after terminal differentiation (Freeman et al, 1994;Padmanabhan et al, 1999). Thus, the proliferation of neuronal progenitor cells proposed in the current study is consistent with the co-localization of cyclin D with newly generated neurons in the TMT-induced injury response (McPherson et al, 2003).…”

“…The mechanism of neuronal death induced by TMT has been linked to apoptosis and necrosis (Bruccoleri and Harry, 2000;Fiedorowicz et al, 2001), inflammation (Bruccoleri et al, 1998;Harry and Lefebvre d'Hellencourt, 2003), and signaling via the cyclooxygenase pathway (Geloso et al, 2002). In addition to the characterization of hippocampal damage, recent work has demonstrated an early elevation of cell proliferation and expression of cell cycle genes within the hippocampus (McPherson et al, 2003) suggestive of injury-induced neurogenesis. This interpretation is substantiated in the current study by the increased proliferation within the dentate regions, the localization of cells within the dentate immunopositive for neurogenesis markers, and the significant repopulation of the dentate region.…”

Novel mechanisms and approaches in the study of neurodegeneration and neuroprotection. A review

“…In a study by McPherson et al (2003) an single dose of TMT (2.0 mg/kg i.p.) was administered to mice at 21 days after birth , to produce the well-known neurotoxin spectrum of TMT, namely acute neuronal necrosis of dentate granule cells with attendant astrocytic hypertrophy and microglial activation.…”

Neurotoxins and neurotoxic species implicated in neurodegeneration

“…In addition, TMT induced enhanced expression of pro-inflammatory cytokines such as IL-1α, IL-6, and TNF-α (McCann et al, 1996;Bruccoleri et al, 1998), increased cell cycle genes cyclin A2, cyclin B1 and cyclin D1 -the latter in regions in which there was evidence of necrosis, and microglia differentiation to a phagocytic phenotype (McPherson et al, 2003). Because increased cycle gene expression was not associated with microglia prolideration (i.e., BrdU incorporation and Ki-67 immunoreactivity), it is hypothesized that the cyclins may promote differentiation of microglia to the phagocytic phenotype (McPherson et al, 2003).…”