Suppression of intrinsic apoptosis by synaptic released zinc

Abstract

Increased physiological electrical activity has been reported to promote cell survival in many neuronal types, but the exact molecular events that underlie the anti-apoptotic effect of synaptic activity are not completely understood. We have found that zinc release in synaptic transmission induced tau hyperphosphorylation, since tau phosphorylation suppress apoptosis (as evidenced by the higher viability and lower level of activated caspase-3 in phosphorylated tau positive neurons), in this study, the effects of synaptic released zinc on apoptosis is investigated. Competent rat brain hippocampus slices and cultured primary neurons were incubated with glutamate or bicuculline/4-aminopyridine (bic/4-AP) to induce bursts of action potential firing, with or without the pre-treatment of Ca-EDTA, a membrane-impermeable zinc chelator. Then the brain slices or neurons were harvested, cell viability was measured by using CCK-8 assay, the expression and activity of apoptotic markers p53 and caspase-3 were detected. Glutamate treatment for 20 minutes have no effect on p53 expression and caspase-3 activity, no cell apoptosis was observed; Bic/4-AP treatment for 3h increased cell viability as previously reported. While pre-incubation with Ca-EDTA in both glutamate and bic/4-AP treated brain slices and primary neurons up-regulated p53 expression and caspase-3 activity, with decreased cell viability, indicating that synaptic released zinc inhibits apoptosis. Synaptic released zinc inhibits intrinsic apoptosis in neurotransmission, however, whether this anti-apoptotic effect is mediated by tau phosphorylation needs to be further explored.