Abstract
The reduced form of vitamin C, ascorbic acid (AA), has been related with gene expression and cell differentiation in the cerebral cortex. In neurons, AA is mainly oxidized to dehydroascorbic acid (DHA); however, DHA cannot accumulate intracellularly because it induces metabolic changes and cell death. In this context, it has been proposed that vitamin C recycling via neuron–astrocyte coupling maintains AA levels and prevents DHA parenchymal accumulation. To date, the role of this mechanism during the outgrowth of neurites is unknown. To stimulate neuronal differentiation, adhered neurospheres treated with AA and retinoic acid (RA) were used. Neuritic growth was analyzed by confocal microscopy, and the effect of vitamin C recycling (bystander effect) in vitro was studied using different cells. AA stimulates neuritic growth more efficiently than RA. However, AA is oxidized to DHA in long incubation periods, generating a loss in the formation of neurites. Surprisingly, neurite growth is maintained over time following co-incubation of neurospheres with cells that efficiently capture DHA. In this sense, astrocytes have high capacity to recycle DHA and stimulate the maintenance of neurites. We demonstrated that vitamin C recycling in vitro regulates the morphology of immature neurons during the differentiation and maturation processes.
Highlights
During the first weeks of postnatal development, cortical neurons undergo dynamic processes of neuronal maturation, such as dendritic spine morphogenesis and synapse formation [1,2,3]
Our work demonstrates that vitamin C recycling, mediated by neuron–astrocyte interactions, regulates extracellular dehydroascorbic acid (DHA) concentrations such that DHA cannot inhibit neurite differentiation
When analyzing Sodium-dependent Vitamin C Transporter 2 (SVCT2) transporter localization, we observed that after 24 h of adhesion, cells with a neuronal phenotype were positive for βIII tubulin and expressed the SVCT2 transporter (Figure 1E)
Summary
During the first weeks of postnatal development, cortical neurons undergo dynamic processes of neuronal maturation, such as dendritic spine morphogenesis and synapse formation [1,2,3]. If cortical neurons are exposed to DHA under conditions of oxidative stress, cell death is induced, which is inhibited in the presence of astrocytes that can recycle DHA from the extracellular environment [19] In this context, it has been postulated that neuron–astrocyte metabolic coupling allows for the maintenance of AA/DHA levels in the cerebral parenchyma, a process known as “vitamin C recycling”. DHA is captured by astrocytes through GLUT1, so DHA is reduced to AA [20,21] To date, this mechanism has only been described in the adult brain, in which neurons and astrocytes are fully mature; the role of vitamin C recycling during the early postnatal development of the cerebral cortex is unknown
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