Vitamin D and Depression: Cellular and Regulatory Mechanisms

Depression is caused by a change in neural activity resulting from an increase in glutamate that drives excitatory neurons and may be responsible for the decline in the activity and number of the GABAergic inhibitory neurons. This imbalance between the excitatory and inhibitory neurons may contribute to the onset of depression. At the cellular level there is an increase in the concentration of intracellular Ca 2+ within the inhibitory neurons that is driven by an increase in entry through the NMDA receptors (NMDARs) and through activation of the phosphoinositide signaling pathway that generates inositol trisphosphate (InsP 3 ) that releases Ca 2+ from the internal stores. The importance of these two pathways in driving the elevation of Ca 2+ is supported by the fact that depression can be alleviated by ketamine that inhibits the NMDARs and scopolamine that inhibits the M1 receptors that drive InsP 3 /Ca 2+ pathway. This increase in Ca 2+ not only contributes to depression but it may also explain why individuals with depression have a strong likelihood of developing Alzheimer’s disease. The enhanced levels of Ca 2+ may stimulate the formation of A β to initiate the onset and progression of Alzheimer9s disease. Just how vitamin D acts to reduce depression is unclear. The phenotypic stability hypothesis argues that vitamin D acts by reducing the increased neuronal levels of Ca 2+ that are driving depression. This action of vitamin D depends on its function to maintain the expression of the Ca 2+ pumps and buffers that reduce Ca 2+ levels, which may explain how it acts to reduce the onset of depression.