Cigarette smoke triggers calcium overload in mouse hippocampal neurons via the ΔFOSB-CACNA2D1 axis to impair cognitive performance

Hongchao Zhang; Huabin Zhou; Xianhe Guo; Guopei Zhang; Mingyang Xiao; Shengwen Wu; Cuihong Jin; Jinghua Yang; Xiaobo Lu

Ecotoxicology and Environmental Safety (Jun 2023)

Cigarette smoke triggers calcium overload in mouse hippocampal neurons via the ΔFOSB-CACNA2D1 axis to impair cognitive performance

Hongchao Zhang,
Huabin Zhou,
Xianhe Guo,
Guopei Zhang,
Mingyang Xiao,
Shengwen Wu,
Cuihong Jin,
Jinghua Yang,
Xiaobo Lu

Affiliations

Hongchao Zhang: Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, People's Republic of China; Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, People's Republic of China
Huabin Zhou: Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, People's Republic of China
Xianhe Guo: Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, People's Republic of China
Guopei Zhang: Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, People's Republic of China; Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, People's Republic of China
Mingyang Xiao: Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, People's Republic of China; Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, People's Republic of China
Shengwen Wu: Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, People's Republic of China; Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, People's Republic of China
Cuihong Jin: Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, People's Republic of China; Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, People's Republic of China
Jinghua Yang: Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, People's Republic of China; Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, People's Republic of China
Xiaobo Lu: Key Laboratory of Environmental Stress and Chronic Disease Control and Prevention, Ministry of Education, China Medical University, Shenyang 110122, People's Republic of China; Department of Toxicology, School of Public Health, China Medical University, Shenyang 110122, People's Republic of China; Correspondence to: Department of Toxicology, School of Public Health, China Medical University, No. 77 Puhe Road, Shenyang North New District, Shenyang 110122, Liaoning Province, People's Republic of China.

Journal volume & issue: Vol. 258
p. 114996

Abstract

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A growing body of evidence shows that cigarette smoking impairs cognitive performance. The 'Calcium Hypothesis' theory of neuronopathies reveals a critical role of aberrant calcium signaling in compromised cognitive functions. However, the underlying implications of abnormalities in calcium signaling in the neurotoxicity induced by cigarette smoke (CS) have not yet been identified. CACNA2D1, an important auxiliary subunit involved in the composition of voltage-gated calcium channels (VGCCs), was reported to affect the calcium signaling in neurons by facilitating VGCCs-mediated Ca2+ influx. ΔFOSB, an alternatively-spliced product of the Fosb gene, is an activity-dependent transcription factor induced robustly in the brain in response to environmental stimuli such as CS. Interestingly, our preliminary bioinformatics analysis revealed a significant co-expression between ΔFOSB and CACNA2D1 in brain tissues of patients with neurodegenerative diseases characterized by progressive cognitive decline. Therefore, we hypothesized that the activation of the ΔFOSB-CACNA2D1 axis in response to CS exposure might cause dysregulation of calcium homeostasis in hippocampal neurons via VGCCs-mediated Ca2+ influx, thereby contributing to cognitive deficits. To this end, the present study established a CS-induced mouse model of hippocampus-dependent cognitive impairment, in which the activation of the ΔFOSB-CACNA2D1 axis accompanied by severe calcium overload was observed in the mouse hippocampal tissues. More importantly, ΔFOSB knockdown-/overexpression-mediated inactivation/activation of the ΔFOSB-CACNA2D1 axis interdicted/mimicked CS-induced dysregulation of calcium homeostasis followed by severe cellular damage in HT22 mouse hippocampal neurons. Mechanistically speaking, a further ChIP-qPCR assay confirmed the physical interaction between transcription factor ΔFOSB and the Cacna2d1 gene promoter, suggesting a direct transcriptional regulation of the Cacna2d1 gene by ΔFOSB. Overall, our current work aims to deliver a unique insight into the neurotoxic mechanisms induced by CS to explore potential targets for intervention.

Published in Ecotoxicology and Environmental Safety

ISSN: 0147-6513 (Print); 1090-2414 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Technology: Environmental technology. Sanitary engineering: Environmental pollution; Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/ecotoxicology-and-environmental-safety

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