The transcriptional factor Neurod1 regulates preconditioned-induced neurogenesis by activating sodium/calcium exchanger NCX1 in ischemic rats

Abstract

Over the last two decades, there has been an increasing interest in understanding the mechanisms underlying neurogenesis as potential neurorestorative strategy triggered by ischemic preconditioning (IPC). Among these mechanisms, neuronal calcium homeostasis plays a fundamental role in supporting neurogenesis. Since sodium/calcium exchangers NCX1 and NCX3 are key effectors of IPC-mediated neuroprotection, this study aimed to investigate their contribution to the activation and maintenance of endogenous neurogenesis induced by IPC. Specifically, in an adult rat model of ischemic preconditioning, we examined whether: (1) IPC+tMCAO modulates the neurogenesis through NCX1 and NCX3 activation in subventricular zone (SVZ) and in the ipsilateral striatum; (2) NCX1 and NCX3 silencing may modulate the expression of "immature" neurons expressing the transcriptional factor NeuroD1 in SVZ; (3) the effects of IPC+tMCAO on the two isoforms, NCX1 and NCX3, are mediated by the transcriptional factor NeuroD1 expressed by "immature" neurons; (4) NeuroD1 directly binds ncx promoter evaluated by luciferase assay. Our findings revealed that, in the SVZ, IPC+tMCAO enhances at the same time either the expression of the neurogenesis marker, NeuroD1, and the expression of NCX1 and NCX3. Furthermore, the silencing of both NCX1 or NCX3 not only abolished the protective effects of IPC+tMCAO, but also impaired neuroblast proliferation, as NeuroD1 upregulation was completely suppressed. More interestingly, NeuroD1 directly binds ncx1 promoter, thus increasing its expression. Collectively, these results demonstrated that the transcriptional factor NeuroD1 regulates IPC+tMCAO-induced neurogenesis in the subventricular zone and in striatum by activating sodium/calcium exchanger ncx1, but not ncx3, in ischemic rats.

Keywords: Ischemic preconditioning; NeuroD1; Neurogenesis; Sodium/calcium exchangers.