Chronic Pb Exposure Induces Anxiety and Depression-like Behaviors in Mice via Excitatory Neuronal Hyperexcitability in Ventral Hippocampal Dentate Gyrus

Abstract

Lead (Pb) is a widespread neurotoxic pollutant. Pb exposure is associated with mood disorders, with no well-established neural mechanisms elucidated. In the present study, we aimed to investigate whether excitatory neurons in the dentate gyrus subregion of the ventral hippocampus (vDG) played a key role in Pb-induced anxiety and depression-like behaviors. C57BL/6 mice were exposed to 100 ppm Pb starting on day 1 of pregnancy until experiments were performed using the offspring. Behavioral studies suggested that chronic Pb exposure triggered anxiety and depression-like behaviors. A combination of electrophysiological, optogenetic, and immunohistochemistry experiments was conducted. Results showed that Pb exposure resulted in excitatory neuronal hyperexcitability in vDG and that the behavioral deficits caused by Pb exposure could be rescued by inhibition of excitatory neuronal activity. Moreover, it was found that the action potential (AP) threshold of excitatory neurons was decreased by electrophysiological recordings. Our study demonstrates a significant role for excitatory neurons in vDG in Pb-induced anxiety and depression-like behaviors in mice, which is likely a result of decreased AP threshold. These outcomes can serve as an important basis for understanding mechanisms of anxiety and depression under environmental Pb exposure and help in the design of therapeutic strategies.