Astrocyte Intracellular Ca2+and TrkB Signaling in the Hippocampus Could Be Involved in the Beneficial Behavioral Effects of Antidepressant Treatment.

Abstract

Although monoaminergic-based antidepressant drugs are largely used to treat major depressive disorder (MDD), their mechanisms are still incompletely understood. Intracellular Ca2+ (iCa2+) and Calmodulin 1(CaM-1) homeostasis have been proposed to participate in the therapeutic effects of these compounds. We investigated whether intra-hippocampal inhibition of CaM-1 would modulate the behavioral responses to chronic treatment with imipramine (IMI) or 7-nitroindazole (7-NI), a selective inhibitor of the neuronal nitric oxide synthase 1 (NOS1) enzyme that shows antidepressant-like effects. We also investigated the interactions of IMI and CaM-1 on transient astrocyte iCa2+ evoked by glutamate stimuli. Intra-hippocampal microinjection of the lentiviral delivered (LV) short hairpin iRNA-driven against the CaM-1 mRNA (LV-shRNA-CaM-1) or the CaM-1 inhibitor N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide (W-7) blocked the antidepressant-like effect of chronic treatment with IMI or 7-NI. The shRNA also inhibited the mRNA expression of the tropomyosin receptor kinase B (TrkB) in the microinjection region. The iCa2+ in ex vivo hippocampus slices stained with fluorescent Ca2+indicator Oregon Green 488 BAPTA-1 revealed that IMI increased the intensity and duration of iCa2+ oscillation and reduced the number of events evoked by glutamate stimuli, evaluated by using CCD imaging and the % ΔF/Fo parameters. The pre-treatment with W-7 fully antagonized this effect. The present results indicate that the behavioral benefits of chronic antidepressant treatment might be associated with astrocyte intracellular Ca2+dynamics and TrkB mRNA expression in the hippocampus.