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 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.