Superfund Research Program
Cellular and Molecular Mechanisms of Cadmium Neurotoxicity
Cadmium (Cd) is a heavy metal of high interest to the Superfund Initiative. Recent epidemiology studies have suggested a possible association between Cd exposure and cognitive, as well as olfactory, impairments in humans. However, studies in animal models were needed to establish a direct causal relationship between Cd exposure and impairments in cognition and olfaction. The Project’s previous studies demonstrated that Cd exposure impairs adult hippocampal neurogenesis and hippocampus-dependent memory in mice. Adult hippocampal neurogenesis is a process in which adult neural progenitor/stem cells (aNPCs) in the subgranular zone (SGZ) of the dentate gyrus (DG) generate functional new neurons in the hippocampus which contributes to hippocampus-dependent learning and memory. The research team’s recent results suggest that Cd exposure impairs adult hippocampal neurogenesis both in vitro and in vivo. This may contribute to Cd-mediated inhibition of hippocampus-dependent learning and memory. The project in year 4 aimed to determine if these adverse effects of Cd exposure can be mitigated by genetically and conditionally enhancing adult neurogenesis. To address this issue, the team utilized the transgenic caMEK5 mouse strain previously developed and characterized. This mouse strain enables researchers to activate adult neurogenesis genetically and conditionally by administering tamoxifen to induce expression of a constitutively active form of MEK5 (caMEK5) in adult neural stem/progenitor cells, which stimulates adult neurogenesis through activation of the endogenous ERK5 MAP kinase pathway. The caMEK5 mice were exposed to 0.6 mg/L Cd through drinking water for 38 weeks. Once impairment of memory was confirmed, tamoxifen was administered to induce caMEK5 expression and to activate adult neurogenesis. Behavior tests were conducted at various time points to monitor hippocampus-dependent memory. Upon completion of the behavior tests, brain tissues were collected for cellular studies of adult hippocampal neurogenesis. Researchers reported that Cd impaired hippocampus-dependent spatial memory and contextual fear memory in mice. These deficits were rescued by the tamoxifen induction of caMEK5 expression. Furthermore, Cd inhibition of adult hippocampal neurogenesis was also reversed. This rescue experiment provides strong evidence for a direct link between Cd-induced impairments of adult hippocampal neurogenesis and hippocampus-dependent memory (Wang 2020). Using a similar approach, the research team also demonstrated a direct link between Cd-induced impairments of adult neurogenesis in the olfactory bulb and olfaction (Wang 2020).