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Transl Psychiatry. 2019 Nov 11;9(1):281. doi: 10.1038/s41398-019-0626-z.

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

Author information

1
Queensland Brain Institute, University of Queensland, St. Lucia, QLD, 4072, Australia.
2
Clem Jones Centre for Ageing Dementia Research, University of Queensland, St. Lucia, QLD, 4072, Australia.
3
Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, 4072, Australia.
4
Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, QLD, 4076, Australia.
5
Department of Biomedicine, Aarhus University, 8000, Aarhus, Denmark.
6
iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, 8000, Aarhus, Denmark.
7
Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, 2300, Copenhagen, Denmark.
8
National Centre for Register-Based Research, Aarhus University, 8000, Aarhus, Denmark.
9
Centre for Integrated Register-based Research, Aarhus University, 8000, Aarhus, Denmark.
10
Brain Research Centre and Department of Biology, Southern University of Science and Technology, Nanshan District, Shenzhen, Guangdong Province, P. R. China.
11
Queensland Brain Institute, University of Queensland, St. Lucia, QLD, 4072, Australia. j.mcgrath@uq.edu.au.
12
Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, QLD, 4076, Australia. j.mcgrath@uq.edu.au.
13
National Centre for Register-Based Research, Aarhus University, 8000, Aarhus, Denmark. j.mcgrath@uq.edu.au.

Abstract

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)2D) 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)2D 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)2D 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)2D-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)2D 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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