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Role of the neural cell adhesion molecule (NCAM) in heavy metal neurotoxicity

Posted on:1999-01-28Degree:Ph.DType:Dissertation
University:Rutgers The State University of New Jersey - New BrunswickCandidate:Dey, Paritosh MarkusFull Text:PDF
GTID:1464390014472083Subject:Health Sciences
Abstract/Summary:
Disorders of neural morphogenesis and cognitive behavior are hallmarks of developmental and adult exposure to toxic metals, but the molecular mechanisms underlying these effects are poorly understood. Growing evidence suggests the involvement of cell adhesion molecules (CAMs), membrane proteins whose proper temporal and spatial expression is critical for cell-cell interactions during cytoarchitectural formation and maintenance of mature synaptic structure.; To examine the role of CAMs in heavy metal neurotoxicity, we examined the effects of methylmercury (MeHg) and trimethyltin (TMT), two well-characterized neurotoxicants, on the temporal expression and posttranslational modification of the neural cell adhesion molecule (NCAM) during brain development and in the adult animal. For developmental studies, rat pups were dosed with 7.0 mg/kg MeHg (s.c.) on alternate days from postnatal days (PND) 3-13 and killed on PNDs 15, 30, and 60. For studies of NCAM in adult brain, mice were administered a single dose of TMT (2.0 or 3.0 mg/kg, i.p.) and killed 6 hours to 21 days later. NCAM expression was assayed in defined brain regions by western blotting, Golgi sialyltransferase activity, and immunocytochemistry. MeHg treatment reduced polysialylated NCAM (PSA-NCAM) expression in cerebellar isolated growth cones at PND 15, while increased PSA-NCAM was observed in purified synaptosomes obtained from forebrain and hippocampal brain regions at PND 15 and 30. Increased expression of "immature" PSA-NCAM was observed by both biochemical and immunocytochemical endpoints in hippocampus at days 15 and 30. In vitro assays confirmed the ability of MeHg to alter sialyltransferase in an age- and brain region-dependent manner. In contrast, TMT treatment of adult mice induced a dramatic loss of hippocampal NCAM immunoreactivity which was associated with marked elevation of proteolytic activity and increased membrane protein turnover.; Inappropriate NCAM expression, particularly at synapses, may reflect defective "maturation" of NCAM or indicate a reactive response of neurons to toxic injury. Altered expression of synaptic NCAM likely contributes to the behavioral and morphological disturbances observed following neurotoxic exposure to metals. These deficits may result from disruption of synapse formation during critical periods of development or from interference with the activity-dependent plasticity of synaptic contacts involved in learning and memory consolidation.
Keywords/Search Tags:NCAM, Cell adhesion, Neural, Adult
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