Antidepressants increase the proliferation of neural precursors in adult dentate gyrus (DG) which is considered to be involved in the therapeutic action of antidepressants. were Roxadustat examined with BrdU immunocytochemistry. AMI had no effect on ADP proliferation but AMI-treated CM increased it. The receptors of GDNF BDNF and FGF2 but not VEGF were expressed in ADP. FGF2 significantly increased ADP proliferation but not BDNF and GDNF. In addition both of a specific inhibitor of FGF receptors and anti-FGF2 antibody significantly counteracted the increasing effect of CM on ADP proliferation. In addition FGF2 in brain is mainly derived Roxadustat from astrocytes that are key components of the neurogenic niches in adult DG. These suggest that AMI may increase ADP proliferation indirectly via PCA and that FGF2 may a potential candidate to mediate such an indirect effect of AMI on ADP proliferation via astrocytes. Introduction Although many antidepressants are currently available up to 30% of patients with major depression are still refractory to them    and the lifetime prevalence of major depression remains 16.2% in the USA . Therefore the development of new antidepressants whose action mechanism is different from existing antidepressants is ardently desired. It has been well established that neurogenesis occurs in the dentate gyrus (DG) of adult hippocampus  . Neurogenesis contains the proliferation of neural precursors the differentiation of neural precursors into neurons and the survival of neural precursors and newly born neurons. In these three phenomena of neurogenesis the proliferation of neural precursors in adult DG is increased by chronic treatments with various classes of antidepressants   . In addition the disruption of the proliferation of neural precursors in adult DG counteracts the Rabbit Polyclonal to HSD11B1. behavioral effects of antidepressants  . These suggest that the increasing effects of antidepressants on the proliferation of neural precursors in adult DG may be involved in the action mechanism of antidepressants and that increasing the proliferation of neural precursors in adult DG may be beneficial to the treatment of depression. However it remains unclear how antidepressants increase the proliferation of neural precursors in adult DG. We have already established the culture system of adult rat DG-derived neural precursors (ADP) . Using ADP we have already shown that four common mood stabilizers such as lithium valproate carbamazepine and lamotrigine have varied direct effects on ADP proliferation differentiation and survival . In contrast to mood stabilizers antidepressants had no direct effect on ADP proliferation differentiation and survival ( and our unpublished data). These suggest that unknown indirect mechanism may mediate the increasing effects of antidepressants on the proliferation of neural precursors in adult DG. As the candidates of such indirect pathways two distinct pathways can be considered; neuron-dependent pathway and astrocyte-dependent pathway. We have already shown that noradrenaline (NA) directly increases ADP proliferation through β2-adrenergic receptor . In addition noradrenergic neurons project from locus coeruleus nucleus to DG  . These suggest that antidepressants may increase the proliferation of neural precursors in adult DG through inhibiting NA transporter in noradrenergic neurons. On the other hand we have recently shown that antidepressants including tricyclic antidepressant amitriptyline (AMI) induce the expression and secretion of brain-derived neurotrophic factor (BDNF) fibroblast growth factor 2 (FGF2) glial cell-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) all of which are known to increase the proliferation of neural precursors in adult DG     from primary cultured astrocytes (PCA) . In addition astrocytes are key components Roxadustat of the neurogenic niches in adult Roxadustat DG  and astrocytes derived from adult hippocampus increase the proliferation of adult hippocampal neural precursors in co-culture . These studies suggest that antidepressants may increase the proliferation of neural precursors in adult DG via inducing the expression and secretion of neurotrophic/growth factors from astrocytes. However it remains unclear whether astrocytes are necessary for the increasing.