1,25(OH)₂D₃ in Brain Function and Neuropsychiatric Disease

1,25(OH)₂D₃ (1,25-dihydroxy-vitamin D3 = calcitriol) is a powerful regulator of mineral metabolism. The hormone increases calcium and phosphate plasma concentrations in part by stimulation of intestinal absorption and renal reabsorption of calcium and phosphate. It is primarily, but not exclusively, produced in the kidney. Renal 1,25(OH)₂D₃ formation is stimulated by calcium and phosphate deficiency and by parathyroid hormone which is up-regulated by hypocalcemia. 1,25(OH)₂D₃ formation is inhibited by fibroblast growth factor FGF23, which is up-regulated by phosphate excess and requires Klotho to become effective. Klotho- or FGF23-deficiency leads to excessive plasma 1,25(OH)₂D₃-, Ca²⁺- and phosphate-concentrations with severe soft tissue calcification and accelerated aging. Tissue calcification and premature aging are prevented by NH₄Cl without affecting 1,25(OH)₂D₃-formation. 1,25(OH)₂D₃ has powerful effects apparently unrelated to mineral metabolism, including anti-inflammatory actions and modification of multiple brain functions. Excessive 1,25(OH)₂D₃ formation in klotho-deficient NH₄Cl-treated mice leads to an amazing surge of exploratory behavior, lack of anxiety and decreased depression, effects dissipated by low vitamin D diet. Conversely, vitamin D deficient mice display reduced explorative behavior, enhanced anxiety, aberrant grooming, submissive social behavior, social neglect and maternal cannibalism. 1,25(OH)₂D₃ is generated in human brain, and acts on diverse structures including prefrontal cortex, hippocampus, cingulate gyrus, thalamus, hypothalamus, and substantia nigra. In neurons 1,25(OH)₂D₃ suppresses oxidative stress, inhibits inflammation, provides neuroprotection, down-regulates a variety of inflammatory mediators and up-regulates a wide variety of neurotrophins. Diseases postulated to be favorably modified by 1,25(OH)₂D₃ include multiple sclerosis, Parkinson´s disease, Alzheimer´s disease, depression, bipolar disorder and schizophrenia. Clearly, substantial additional experimentation is required to fully understand the neuro-psycho-pathophysiological role of 1,25(OH)₂D₃ and to exploit 1,25(OH)₂D₃ or related agonists in the treatment of neuro-psychiatric disorders.