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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...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
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
Descripción
Sumario: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.