Zinc (Zn), an essential trace element, is secreted by synaptic vesicles during neuronal excitation and plays several critical roles in neuronal information processing. However, excess Zn ion (Zn(2+)) is neurotoxic and has a causative role in the pathogenesis of vascular dementia. Here, we investigated the molecular mechanism of Zn(2+)-induced neurotoxicity by using immortalized hypothalamic neurons (GT1-7 cells), which are more vulnerable than other neuronal cells to Zn(2+). We examined the effects of other metal ions on the Zn(2+)-induced neurotoxicity in these cells and found that sub-lethal concentrations of copper ion (Cu(2+)) markedly exacerbated Zn(2+)-induced neurotoxicity. The co-administration of Cu(2+) and Zn(2+) also significantly increased the expression of genes related to the endoplasmic reticulum's stress response, including CHOP, GADD34, and ATF4. Similar to Zn(2+), Cu(2+) is stored in presynaptic vesicles and secreted during neuronal excitation. Thus, based on our results, we hypothesize here that Cu(2+) interacts with Zn(2+) in the synapse to synergistically promote neuronal death and significantly influence the pathogenesis of vascular dementia.