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

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. AFOSB, 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 coexpression between AFOSB and CACNA2D1 in brain tissues of patients with neurodegenerative diseases characterized by progressive cognitive decline. Therefore, we hypothesized that the activation of the AFOSB-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 AFOSB-CACNA2D1 axis accompanied by severe calcium overload was observed in the mouse hippocampal tissues. More importantly, AFOSB knockdown-/overexpression-mediated inactivation/activation of the AFOSB-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 AFOSB and the Cacna2d1 gene promoter, suggesting a direct transcriptional regulation of the Cacna2d1 gene by AFOSB. Overall, our current work aims to deliver a unique insight into the neurotoxic mechanisms induced by CS to explore potential targets for intervention.

Automated summary

An increasing amount of evidence suggests that cigarette smoking has negative effects on cognitive performance, possibly through the disruption of calcium signaling. This study investigates the implications of abnormalities in calcium signaling induced by cigarette smoke (CS) exposure. The activation of the AFOSB-CACNA2D1 axis, which plays a role in calcium homeostasis, was observed in the hippocampal tissues of a mouse model of CS-induced cognitive impairment. Furthermore, the study found that AFOSB directly regulates the transcription of the Cacna2d1 gene. Overall, this research provides insight into the neurotoxic mechanisms of CS and identifies potential targets for intervention.