The cytoarchitecture of the adult central nervous system is expressed by proteins specific to individual cell types. In this investigation, a subclass of these proteins, the neuron-specific phosphoproteins, was examined after the administration of trimethyltin (TMT), a neurotoxicant which preferentially damages neurons in limbic structures. After acute administration of TMT (0.0-9.0 mg/kg i.v.), effects on neuronal phosphoproteins were examined by three separate techniques: endogenous phosphorylation of total synaptic membrane proteins; radiometric assay of synapsin I, a neuron-specific phosphoprotein associated with synaptic vesicles; and radioimmunoassay of synapsin I and protein III, another synapse specific, synaptic vesicle-localized phosphoprotein. All three procedures gave similar results. TMT caused dose- and time-dependent decreases in hippocampal phosphoproteins. These effects were large in magnitude and were still evident 14 weeks after exposure to TMT. Microdissection of slices of dorsal hippocampus did not reveal significant regional differences in the extent to which TMT affected synapsin I. Phosphoproteins in frontal cortex, unlike those in hippocampus, were not affected by TMT. Our findings are consistent with the neuropathological effects of this compound and suggest that neuron-specific phosphoproteins may be useful biochemical indicators of neurotoxicity.