TRIMETHYLTIN EXPOSURE IN THE RAT INDUCES DELAYED CHANGES IN BRAIN-DERIVED NEUROTROPHIC FACTOR, FOS AND HEAT-SHOCK-PROTEIN-70

Trimethyltin chloride (TMT) treatment in adult rats leads to limbic br ain lesions that are detectable with classical neuropathological techn iques 3 days after exposure. In particular, the hippocampal cells of t he CA3c region are affected. The temporal and regional characteristics of TMT toxicity as reflected in changes of activity-dependent factors were studied in adult male Sprague-Dawley rats using quantitative in situ hybridization and immunohistochemistry. No significant alteration s in BDNF mRNA were defected in hippocampus and cerebral cortex 1 and 4 h after 8 mg TMT/kg. Three days after TMT, a significant increase in BDNF mRNA was detected in CA1, and increases in BDNF mRNA were also s een in cortical layers. An increase in BDNF hybridization signal was s een over scattered neurons within and outside CA3c at 3 days. Four h a fter 8 mg TMT/kg, BDNF immunoreactivity was reduced in the pyramidal c ells of the CA3c and CA1 regions as well as in the dentate gyrus. No s ignificant change in BDNF immunoreactivity was seen in hippocampus or cerebral cortex 3 days after TMT. BDNF interacts with the high-affinit y receptor tyrosine kinase B (trkB). No immediate alteration in trkB m RNA was seen in hippocampus or cerebral cortex after 8 mg TMT/kg, whil e at 3 days trkB mRNA was significantly reduced in the CA3c pyramidal cell layer. No changes could be detected in neurotrophin-3 mRNA at eit her 1, 4 h or 3 days after TMT Three days after 8 mg TMT/kg, a major i nduction of hsp70 mRNA occurred in a subset of neurons in the CA3c reg ion, concomitant with an increased expression of c-fos mRNA as well as Fos protein in the hilar region of hippocampus. Hence, an early and t ransient decrease in BDNF appears to occur after TMT exposure, which i s succeeded at 3 days by increases in BDNF, c-fos and hsp 70 mRNAs, co ncomitant with a decrease in trkB mRNA in regions known to be vulnerab le to TMT. These results demonstrate that TMT causes a delayed, spatia lly restricted increase in activity-dependent gene expression, making TMT-induced disturbances an interesting model of neurodegenerative eve nts. (C) 1997 Inter Press, Inc.