We examined the link of hippocampal Zn to the functional impairments with aging using senescence-accelerated mouse prone 10 (SAMP10) with deficits in learning and memory. Zn in hippocampal mossy fiber pathway was less distributed in aged SAMP10 than that in the age-matched control. Furthermore, expression of Zn transporter 3, ZnT3, which plays to accumulate Zn in synaptic vesicles in the mossy fiber pathway, was markedly reduced in the hippocampal region even in young SAMP10. Moreover, excessive presynaptic release of glutamate as well as glycine and expression of glial fibrillary acidic protein, a marker of neuronal cell injury, were observed in the hippocampus of aged SAMP10 compared to the control. The present results suggest that age-dependent deficiencies of Zn in synaptic vesicles of the mossy fiber pathway induced by low expression of ZnT3 cause glutamatergic excitotoxicity in the hippocampal neurons and the deterioration of learning and memory in SAMP10. (C) 2000 Academic Press.