Cadmium exposure impairs adult neurogenesis, cognition, and olfactory memory in mice

Abstract

Cadmium (Cd) is a ubiquitous toxic heavy metal of high interest to the Superfund initiative. It causes toxic effects to many organs, including kidney, liver, lung, and bone. Cd is also a potential neurotoxicant. Recently, several epidemiology studies have found an association between Cd exposure and cognitive as well as olfactory impairments in humans. However, studies in animal models are needed to establish a direct causal relationship between Cd exposure and impaired cognitive and olfactory functions. In this study, by exposing adult male mice to 3 mg/L Cd through drinking water, I found that Cd exposure induces persistent impairments of hippocampus-dependent learning and memory in the novel object location test, the T-maze test, and the contextual fear memory test, but not in the water maze test in young adult mice. In addition, I also found that Cd exposure impairs olfactory memory in mice. Adult neurogenesis is a process that generates functional new neurons from adult neural progenitor/stem cells (aNPCs). It is spatially restricted to two specific regions in the adult brain: the subgranular zone (SGZ) in the dentate gyrus of the hippocampus and the subventricular zone (SVZ) along the lateral ventricles. These adult-born neurons in the SGZ and SVZ contribute to hippocampus-dependent memory and olfaction, respectively. The process of adult neurogenesis can be modulated by various extracellular and intracellular stimuli, but the studies on how neurotoxicants affect this important process are still lacking. Using an in vitro model of adult neurogenesis, I found that Cd significantly increases apoptosis, inhibits proliferation, and impairs spontaneous neuronal differentiation. In addition, activation of JNK and p38 MAPK signaling pathways are involved in Cd cytotoxicity in aNPCs. Furthermore, I also observed that adult Cd exposure impairs SGZ and SVZ adult neurogenesis in vivo. Additionally, by using caMEK5 mice, a gain-of-function knock-in transgenic mouse line that allows inducible and conditional activation of adult neurogenesis, I found that enhancing adult neurogenesis by genetic manipulation after Cd exposure can rescue mice from Cd-induced impairments of cognition and olfactory memory. Together, these results suggest that Cd exposure impairs hippocampus-dependent learning and memory, as well as olfactory memory in mice. In addition, Cd can directly act on aNPCs to impair critical processes of adult neurogenesis. Furthermore, Cd-induced impairments of cognition and olfaction in mice can be rescued by inducible and conditional enhancement of adult neurogenesis. My research provides the first, clear demonstration of Cd neurotoxicity on cognitive and olfactory functions in an animal model and established a causal relationship between Cd-impaired adult neurogenesis and cognitive as well as olfactory deficits in mice. It provides new insights regarding Cd neurotoxicity and adds useful information for Cd risk assessment.