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1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex
Schizophrenia has been associated with a range of genetic and environmental risk factors. Here we explored a link between two risk factors that converge on a shared neurobiological pathway. Recent genome-wide association studies (GWAS) have identified risk variants in genes that code for L-type volt...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848150/ https://www.ncbi.nlm.nih.gov/pubmed/31712549 http://dx.doi.org/10.1038/s41398-019-0626-z |
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author | Gooch, Helen Cui, Xiaoying Anggono, Victor Trzaskowski, Maciej Tan, Men Chee Eyles, Darryl W. Burne, Thomas H. J. Jang, Se Eun Mattheisen, Manuel Hougaard, David M. Pedersen, Bent Nørgaard Cohen, Arieh Mortensen, Preben B. Sah, Pankaj McGrath, John J. |
author_facet | Gooch, Helen Cui, Xiaoying Anggono, Victor Trzaskowski, Maciej Tan, Men Chee Eyles, Darryl W. Burne, Thomas H. J. Jang, Se Eun Mattheisen, Manuel Hougaard, David M. Pedersen, Bent Nørgaard Cohen, Arieh Mortensen, Preben B. Sah, Pankaj McGrath, John J. |
author_sort | Gooch, Helen |
collection | PubMed |
description | Schizophrenia has been associated with a range of genetic and environmental risk factors. Here we explored a link between two risk factors that converge on a shared neurobiological pathway. Recent genome-wide association studies (GWAS) have identified risk variants in genes that code for L-type voltage-gated calcium channels (L-VGCCs), while epidemiological studies have found an increased risk of schizophrenia in those with neonatal vitamin D deficiency. The active form of vitamin D (1,25(OH)(2)D) is a secosteroid that rapidly modulates L-VGCCs via non-genomic mechanisms in a range of peripheral tissues, though its non-genomic effects within the brain remain largely unexplored. Here we used calcium imaging, electrophysiology and molecular biology to determine whether 1,25(OH)(2)D non-genomically modulated L-VGCCs in the developing prefrontal cortex, a region widely implicated in schizophrenia pathophysiology. Wide-field Ca(2+) imaging revealed that physiological concentrations of 1,25(OH)(2)D rapidly enhanced activity-dependent somatic Ca(2+) levels in a small subset of neurons in the developing PFC, termed vitamin D-responsive neurons (VDRNs). Somatic nucleated patch recordings revealed a rapid, 1,25(OH)(2)D-evoked increase in high-voltage-activated (HVA) Ca(2+) currents. Enhanced activity-dependent Ca(2+) levels were mediated by L-VGCC but not associated with any changes to Cacna1c (L-VGCC pore-forming subunit) mRNA expression. Since L-VGCC activity is critical to healthy neurodevelopment, these data suggest that suboptimal concentrations of 1,25(OH)(2)D could alter brain maturation through modulation of L-VGCC signalling and as such may provide a parsimonious link between epidemiologic and genetic risk factors for schizophrenia. |
format | Online Article Text |
id | pubmed-6848150 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-68481502019-11-14 1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex Gooch, Helen Cui, Xiaoying Anggono, Victor Trzaskowski, Maciej Tan, Men Chee Eyles, Darryl W. Burne, Thomas H. J. Jang, Se Eun Mattheisen, Manuel Hougaard, David M. Pedersen, Bent Nørgaard Cohen, Arieh Mortensen, Preben B. Sah, Pankaj McGrath, John J. Transl Psychiatry Article Schizophrenia has been associated with a range of genetic and environmental risk factors. Here we explored a link between two risk factors that converge on a shared neurobiological pathway. Recent genome-wide association studies (GWAS) have identified risk variants in genes that code for L-type voltage-gated calcium channels (L-VGCCs), while epidemiological studies have found an increased risk of schizophrenia in those with neonatal vitamin D deficiency. The active form of vitamin D (1,25(OH)(2)D) is a secosteroid that rapidly modulates L-VGCCs via non-genomic mechanisms in a range of peripheral tissues, though its non-genomic effects within the brain remain largely unexplored. Here we used calcium imaging, electrophysiology and molecular biology to determine whether 1,25(OH)(2)D non-genomically modulated L-VGCCs in the developing prefrontal cortex, a region widely implicated in schizophrenia pathophysiology. Wide-field Ca(2+) imaging revealed that physiological concentrations of 1,25(OH)(2)D rapidly enhanced activity-dependent somatic Ca(2+) levels in a small subset of neurons in the developing PFC, termed vitamin D-responsive neurons (VDRNs). Somatic nucleated patch recordings revealed a rapid, 1,25(OH)(2)D-evoked increase in high-voltage-activated (HVA) Ca(2+) currents. Enhanced activity-dependent Ca(2+) levels were mediated by L-VGCC but not associated with any changes to Cacna1c (L-VGCC pore-forming subunit) mRNA expression. Since L-VGCC activity is critical to healthy neurodevelopment, these data suggest that suboptimal concentrations of 1,25(OH)(2)D could alter brain maturation through modulation of L-VGCC signalling and as such may provide a parsimonious link between epidemiologic and genetic risk factors for schizophrenia. Nature Publishing Group UK 2019-11-11 /pmc/articles/PMC6848150/ /pubmed/31712549 http://dx.doi.org/10.1038/s41398-019-0626-z Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Gooch, Helen Cui, Xiaoying Anggono, Victor Trzaskowski, Maciej Tan, Men Chee Eyles, Darryl W. Burne, Thomas H. J. Jang, Se Eun Mattheisen, Manuel Hougaard, David M. Pedersen, Bent Nørgaard Cohen, Arieh Mortensen, Preben B. Sah, Pankaj McGrath, John J. 1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex |
title | 1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex |
title_full | 1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex |
title_fullStr | 1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex |
title_full_unstemmed | 1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex |
title_short | 1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex |
title_sort | 1,25-dihydroxyvitamin d modulates l-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848150/ https://www.ncbi.nlm.nih.gov/pubmed/31712549 http://dx.doi.org/10.1038/s41398-019-0626-z |
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