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SVCT2 Overexpression and Ascorbic Acid Uptake Increase Cortical Neuron Differentiation, Which Is Dependent on Vitamin C Recycling between Neurons and Astrocytes

During brain development, sodium–vitamin C transporter (SVCT2) has been detected primarily in radial glial cells in situ, with low-to-absent expression in cerebral cortex neuroblasts. However, strong SVCT2 expression is observed during the first postnatal days, resulting in increased intracellular c...

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Autores principales: Salazar, Katterine, Espinoza, Francisca, Cerda-Gallardo, Gustavo, Ferrada, Luciano, Magdalena, Rocío, Ramírez, Eder, Ulloa, Viviana, Saldivia, Natalia, Troncoso, Ninoschka, Oviedo, María José, Barahona, María José, Martínez, Fernando, Nualart, Francisco
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465431/
https://www.ncbi.nlm.nih.gov/pubmed/34573045
http://dx.doi.org/10.3390/antiox10091413
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author Salazar, Katterine
Espinoza, Francisca
Cerda-Gallardo, Gustavo
Ferrada, Luciano
Magdalena, Rocío
Ramírez, Eder
Ulloa, Viviana
Saldivia, Natalia
Troncoso, Ninoschka
Oviedo, María José
Barahona, María José
Martínez, Fernando
Nualart, Francisco
author_facet Salazar, Katterine
Espinoza, Francisca
Cerda-Gallardo, Gustavo
Ferrada, Luciano
Magdalena, Rocío
Ramírez, Eder
Ulloa, Viviana
Saldivia, Natalia
Troncoso, Ninoschka
Oviedo, María José
Barahona, María José
Martínez, Fernando
Nualart, Francisco
author_sort Salazar, Katterine
collection PubMed
description During brain development, sodium–vitamin C transporter (SVCT2) has been detected primarily in radial glial cells in situ, with low-to-absent expression in cerebral cortex neuroblasts. However, strong SVCT2 expression is observed during the first postnatal days, resulting in increased intracellular concentration of vitamin C. Hippocampal neurons isolated from SVCT2 knockout mice showed shorter neurites and low clustering of glutamate receptors. Other studies have shown that vitamin C-deprived guinea pigs have reduced spatial memory, suggesting that ascorbic acid (AA) and SVCT2 have important roles in postnatal neuronal differentiation and neurite formation. In this study, SVCT2 lentiviral overexpression induced branching and increased synaptic proteins expression in primary cultures of cortical neurons. Analysis in neuroblastoma 2a (Neuro2a) and human subventricular tumor C3 (HSVT-C3) cells showed similar branching results. SVCT2 was mainly observed in the cell membrane and endoplasmic reticulum; however, it was not detected in the mitochondria. Cellular branching in neuronal cells and in a previously standardized neurosphere assay is dependent on the recycling of vitamin C or reduction in dehydroascorbic acid (DHA, produced by neurons) by glial cells. The effect of WZB117, a selective glucose/DHA transporter 1 (GLUT1) inhibitor expressed in glial cells, was also studied. By inhibiting GLUT1 glial cells, a loss of branching is observed in vitro, which is reproduced in the cerebral cortex in situ. We concluded that vitamin C recycling between neurons and astrocyte-like cells is fundamental to maintain neuronal differentiation in vitro and in vivo. The recycling activity begins at the cerebral postnatal cortex when neurons increase SVCT2 expression and concomitantly, GLUT1 is expressed in glial cells.
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spelling pubmed-84654312021-09-27 SVCT2 Overexpression and Ascorbic Acid Uptake Increase Cortical Neuron Differentiation, Which Is Dependent on Vitamin C Recycling between Neurons and Astrocytes Salazar, Katterine Espinoza, Francisca Cerda-Gallardo, Gustavo Ferrada, Luciano Magdalena, Rocío Ramírez, Eder Ulloa, Viviana Saldivia, Natalia Troncoso, Ninoschka Oviedo, María José Barahona, María José Martínez, Fernando Nualart, Francisco Antioxidants (Basel) Article During brain development, sodium–vitamin C transporter (SVCT2) has been detected primarily in radial glial cells in situ, with low-to-absent expression in cerebral cortex neuroblasts. However, strong SVCT2 expression is observed during the first postnatal days, resulting in increased intracellular concentration of vitamin C. Hippocampal neurons isolated from SVCT2 knockout mice showed shorter neurites and low clustering of glutamate receptors. Other studies have shown that vitamin C-deprived guinea pigs have reduced spatial memory, suggesting that ascorbic acid (AA) and SVCT2 have important roles in postnatal neuronal differentiation and neurite formation. In this study, SVCT2 lentiviral overexpression induced branching and increased synaptic proteins expression in primary cultures of cortical neurons. Analysis in neuroblastoma 2a (Neuro2a) and human subventricular tumor C3 (HSVT-C3) cells showed similar branching results. SVCT2 was mainly observed in the cell membrane and endoplasmic reticulum; however, it was not detected in the mitochondria. Cellular branching in neuronal cells and in a previously standardized neurosphere assay is dependent on the recycling of vitamin C or reduction in dehydroascorbic acid (DHA, produced by neurons) by glial cells. The effect of WZB117, a selective glucose/DHA transporter 1 (GLUT1) inhibitor expressed in glial cells, was also studied. By inhibiting GLUT1 glial cells, a loss of branching is observed in vitro, which is reproduced in the cerebral cortex in situ. We concluded that vitamin C recycling between neurons and astrocyte-like cells is fundamental to maintain neuronal differentiation in vitro and in vivo. The recycling activity begins at the cerebral postnatal cortex when neurons increase SVCT2 expression and concomitantly, GLUT1 is expressed in glial cells. MDPI 2021-09-03 /pmc/articles/PMC8465431/ /pubmed/34573045 http://dx.doi.org/10.3390/antiox10091413 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Salazar, Katterine
Espinoza, Francisca
Cerda-Gallardo, Gustavo
Ferrada, Luciano
Magdalena, Rocío
Ramírez, Eder
Ulloa, Viviana
Saldivia, Natalia
Troncoso, Ninoschka
Oviedo, María José
Barahona, María José
Martínez, Fernando
Nualart, Francisco
SVCT2 Overexpression and Ascorbic Acid Uptake Increase Cortical Neuron Differentiation, Which Is Dependent on Vitamin C Recycling between Neurons and Astrocytes
title SVCT2 Overexpression and Ascorbic Acid Uptake Increase Cortical Neuron Differentiation, Which Is Dependent on Vitamin C Recycling between Neurons and Astrocytes
title_full SVCT2 Overexpression and Ascorbic Acid Uptake Increase Cortical Neuron Differentiation, Which Is Dependent on Vitamin C Recycling between Neurons and Astrocytes
title_fullStr SVCT2 Overexpression and Ascorbic Acid Uptake Increase Cortical Neuron Differentiation, Which Is Dependent on Vitamin C Recycling between Neurons and Astrocytes
title_full_unstemmed SVCT2 Overexpression and Ascorbic Acid Uptake Increase Cortical Neuron Differentiation, Which Is Dependent on Vitamin C Recycling between Neurons and Astrocytes
title_short SVCT2 Overexpression and Ascorbic Acid Uptake Increase Cortical Neuron Differentiation, Which Is Dependent on Vitamin C Recycling between Neurons and Astrocytes
title_sort svct2 overexpression and ascorbic acid uptake increase cortical neuron differentiation, which is dependent on vitamin c recycling between neurons and astrocytes
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8465431/
https://www.ncbi.nlm.nih.gov/pubmed/34573045
http://dx.doi.org/10.3390/antiox10091413
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