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

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.

• Authors: Helen Gooch, Xiaoying Cui, Victor Anggono, Maciej Trzaskowski, Men Chee Tan, Darryl W Eyles, Thomas H J Burne, Se Eun Jang, Manuel Mattheisen, David M Hougaard, Bent Nørgaard Pedersen, Arieh Cohen, Preben B Mortensen, Pankaj Sah, John J McGrath
• Journal: Translational psychiatry (Transl Psychiatry) Vol. 9 Issue 1 Pg. 281 (11 11 2019) ISSN: 2158-3188 [Electronic] United States
• PMID: 31712549 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channels, L-Type
• Vitamin D
• 1,25-dihydroxyvitamin D

Topics

• Animals
• Calcium Channels, L-Type (physiology)
• Calcium Signaling
• Female
• Male
• Mice
• Mice, Inbred BALB C
• Neurogenesis (physiology)
• Neurons (physiology)
• Prefrontal Cortex (growth & development, physiology)
• Vitamin D (analogs & derivatives, physiology)