Abstract
Connexin43 (Cx43) is highly expressed in astrocytes (AS), and its expression is reduced in the prefrontal cortex of depressive patients. We have previously demonstrated amitriptyline (AMI), a tricyclic antidepressant, increased the expression of brain-derived neurotrophic factor (BDNF) mediated by lysophosphatidic acid (LPA) receptors. Present study examined the detailed mechanism involved in these responses. Primary cultured AS were prepared from the cerebral cortex of neonatal Wistar rats. The expression of Cx43 was downregulated with RNA interference. The expression of mRNA and protein were measured by real-time PCR and western blotting, respectively. Protein kinase C (PKC) activity was measured by using the assay kit. The enhancement of BDNF expression in Cx43-knockdown (KD) AS was suppressed by inhibition of extracellular signal-regulated kinase (ERK) and PKC which were known as the downstream of LPA receptors. Moreover, ERK phosphorylation and PKC activity were increased by treatment with AMI, which were also enhanced in Cx43-KD AS. Present study revealed reduced Cx43 expression potentiated the AMI-induced BDNF expression by enhancement of intracellular signaling in cortical AS. These results indicate the downregulation of Cx43 observed in the depressive patients might contribute to therapeutic effect of antidepressants.
