Retinoic acid signalling in neuropsychiatric disease: possible markers and treatment agents

Retinoic acid is the transcriptionally active product of vitamin A, potentially controlling expression of several hundred genes through activation of specific nuclear receptors. The retinoic acid receptors (RARs) are expressed through much of the adult brain; in contrast the ligand for these receptors is much more restricted in its extent of expression. Non-liganded RARs likely control function through transcriptional repression whereas ligand activated receptors probably regulate more restricted functions including neuroplasticity and neurogenesis. Deregulation of retinoic acid signalling through application of excess levels of this ligand have been associated with depression while genetic and anatomical evidence has linked retinoic acid with the neurodevelopmental hypothesis of schizophrenia and autism. The RARs frequently act in conjunction with the second class of retinoid receptors, the retinoid X receptors (RXRs). These RXRs heterodimerize with other classes of nuclear receptors, including the thyroid hormone receptor which, like those for retinoic acid, are associated with schizophrenia and depression. It is possible that drugs that act on RXRs may be particularly effective in psychiatric disease by acting simultaneously on several nuclear receptor signalling pathways.