1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex

被引:31
作者
Gooch, Helen [1 ]
Cui, Xiaoying [1 ]
Anggono, Victor [1 ,2 ]
Trzaskowski, Maciej [3 ]
Tan, Men Chee [1 ,2 ]
Eyles, Darryl W. [1 ,4 ]
Burne, Thomas H. J. [1 ,4 ]
Jang, Se Eun [1 ,2 ]
Mattheisen, Manuel [5 ,6 ]
Hougaard, David M. [6 ,7 ]
Pedersen, Bent Norgaard [7 ]
Cohen, Arieh [7 ]
Mortensen, Preben B. [6 ,8 ,9 ]
Sah, Pankaj [1 ,10 ,11 ]
McGrath, John J. [1 ,4 ,8 ]
机构
[1] Univ Queensland, Queensland Brain Inst, St Lucia, Qld 4072, Australia
[2] Univ Queensland, Clem Jones Ctr Ageing Dementia Res, St Lucia, Qld 4072, Australia
[3] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia
[4] Queensland Ctr Mental Hlth Res, Pk Ctr Mental Hlth, Wacol, Qld 4076, Australia
[5] Aarhus Univ, Dept Biomed, DK-8000 Aarhus, Denmark
[6] Lundbeck Fdn Initiat Integrat Psychiat Res, iPSYCH, DK-8000 Aarhus, Denmark
[7] Statens Serum Inst, Ctr Neonatal Screening, Dept Congenital Disorders, DK-2300 Copenhagen, Denmark
[8] Aarhus Univ, Natl Ctr Register Based Res, DK-8000 Aarhus, Denmark
[9] Aarhus Univ, Ctr Integrated Register Based Res, DK-8000 Aarhus, Denmark
[10] Southern Univ Sci & Technol, Brain Res Ctr, Shenzhen, Guangdong, Peoples R China
[11] Southern Univ Sci & Technol, Dept Biol, Shenzhen, Guangdong, Peoples R China
基金
新加坡国家研究基金会; 澳大利亚研究理事会; 澳大利亚国家健康与医学研究理事会;
关键词
VITAMIN-D DEFICIENCY; PSYCHIATRIC-DISORDERS; BETA-SUBUNIT; RAT; SCHIZOPHRENIA; RISK; METAANALYSIS; EXPRESSION; ALTERS; PHOSPHORYLATION;
D O I
10.1038/s41398-019-0626-z
中图分类号
R749 [精神病学];
学科分类号
100205 ;
摘要
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 Ca2+ imaging revealed that physiological concentrations of 1,25(OH)(2)D rapidly enhanced activity-dependent somatic Ca2+ 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) Ca2+ currents. Enhanced activity-dependent Ca2+ 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.
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页数:10
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