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.