Abstract
A viewpoint focusing on the interaction between neurons and glia is important for elucidating the pathophysiology and developing therapeutics in psychiatric disorders. We focus on glial cell line‐derived neurotrophic factor (GDNF) among the multiple neurotrophic factors stored in astrocytes, involved in mood disorder patients. Especially classical tricyclic antidepressants have been found to act directly on astrocytes and induce GDNF expression by a mechanism different from that of monoamines and acetylcholine. Furthermore, we found that the antidepressant target molecule is lysophosphatidic acid (LPA) receptor 1, which is one of the G protein‐coupled receptors of lysophospholipids. Tricyclic antidepressants are prototypes of antidepressants found by chance in the 1950s, and are still showing clinical efficacy over SSRIs and SNRIs in severe and refractory patients, and the high risk of manic change. Its pharmacological effects may be associated with potent antidepressant effects. In mouse brain, LPA1 receptor expression was different depending on the site and was localized to astrocytes and oligodendrocytes. In addition, the concentration of autotaxin (ATX) , which is an LPA synthase, was significantly decreased in the blood and cerebrospinal fluid of depressed patients, and was significantly correlated with the depressive symptoms and the course of treatment. Since LPA is associated with neurogenesis, angiogenesis and inflammation, and LPA1 receptor knockout mice exhibit depressive like behavior, the ATX/LPA/LPA1 receptor‐mediated lysophospholipid cascade is the potential to become a new molecular basis for the pathophysiology of mood disorders and develop therapeutics. No potential conflicts of interest were disclosed.
