MICROGLIAL RESPONSIVENESS AS A SENSITIVE MARKER FOR TRIMETHYLTIN (TMT) NEUROTOXICITY

Activation of microglia is a well-documented phenomenon associated wit h diverse pathological conditions of the central nervous system. In or der to investigate the involvement of microglial cells in the neurotox ic action of the heavy metal compound trimethyltin, three-dimensional brain cell cultures were treated during an early developmental period, using concentrations at or below the limit of cytotoxicity. Microglia l cells were studied by cytochemical staining, using horseradish perox idase-conjugated B4 isolectin (GSI-B4). In parallel, neurotoxic effect s were assessed by determining the content of synaptophysin and synaps in I, both in the total homogenates and in the synaptosomal fraction o f the cultures. Changes in the content of the specific growth cone pro tein, GAP-43, were also analyzed. It was found that low, non-cytotoxic concentrations of TMT (10(-9) to 10(-8) M) caused a significant incre ase in the number and/or the clustering of microglial cells. A decreas e in the synaptic protein (synapsin I, synaptophysin) content was dete cted at 10(-8) M of TMT in synaptosomal fractions, whereas in the tota l homogenates, changes in synaptic proteins and GAP-43 were observed o nly at the cytotoxic TMT concentration (10(-6) M). Although it remains to be shown whether the microglial response is caused by direct or in direct action of TMT, the present findings show that microglial respon siveness can be detected prior to any sign of neuronal degeneration, a nd may serve as a sensitive indicator for heavy metal neurotoxicity in the brain.