ABSTRACT
Preclinical and clinical studies suggest that neuronal muscarinic acetylcholine receptor (M-AchR) antagonists have antidepressant-like properties. Despite the recent interest in bicaudal C homolog 1 gene (BICC1) as a target for the treatment of depression, the upstream signaling molecules that regulate BICC1 are unknown, and very few studies have addressed the involvement of BICC1 in the antidepressant-like effects of the selective M1-AchR inhibitor, biperiden. Growing evidence indicates that activation of brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase receptor B (TrkB) signaling may be involved in antidepressant-like activities. In this study, we investigated the role of BDNF/TrkB signaling in the regulation of BICC1 expression in the chronic unpredictable stress (CUS) mouse model of depression. Furthermore, we also examined whether BDNF/TrkB signaling contributes to the antidepressant-like effects of biperiden via down-regulation of BICC1 in the hippocampus and prefrontal cortex of mice. Our current data show that CUS exposure induced significant depression-like behaviors, down-regulation of BDNF/TrkB signaling and up-regulation of BICC1 in the hippocampus and prefrontal cortex of mice. However, biperiden significantly alleviated the CUS-induced abnormalities. Moreover, we found that the effects of biperiden were antagonized by pretreatment with the TrkB antagonist K252a. Our results indicate that BDNF/TrkB signaling may be the major upstream mediator of BICC1 involvement in the antidepressant-like effects of biperiden.
Subject(s)
Antidepressive Agents/therapeutic use , Biperiden/therapeutic use , Brain-Derived Neurotrophic Factor/metabolism , Hippocampus/metabolism , Prefrontal Cortex/metabolism , RNA-Binding Proteins/biosynthesis , Receptor, trkB/metabolism , Animals , Antidepressive Agents/pharmacology , Biperiden/pharmacology , Brain-Derived Neurotrophic Factor/antagonists & inhibitors , Carbazoles/pharmacology , Depression/drug therapy , Depression/metabolism , Hippocampus/drug effects , Indole Alkaloids/pharmacology , Locomotion/drug effects , Locomotion/physiology , Male , Mice , Mice, Inbred ICR , Prefrontal Cortex/drug effects , Receptor, trkB/antagonists & inhibitors , Signal Transduction/drug effects , Signal Transduction/physiology , Stress, Psychological/drug therapy , Stress, Psychological/metabolism , Treatment OutcomeABSTRACT
Amyloid-beta (Aß) interacts with the serine/threonine protein kinase AKT (also known as protein kinase B)/glycogen synthase kinase 3ß (GSK3ß) pathway and deactivates GSK3ß signaling, which result in microtubule protein tau phosphorylation. Atorvastatin, a HMG-CoA reductase inhibitor, has been proven to improve learning and memory performance, reduce Aß and phosphorylated tau levels in mouse model of Alzheimer's disease (AD). However, it still remains unclear whether atorvastatin is responsible for regulation of AKT/GSK3ß signaling and contributes to subsequent down-regulation of Aß1-42 and phosphorylated tau in APP/PS1 transgenic (Tg APP/PS1) mice. Herein, we aimed to investigate the possible impacts of atorvastatin (10 mg/kg, p.o.) on the memory deficit by behavioral tests and changes of AKT/GSK3ß signaling in hippocampus and prefrontal cortex by western blot test in Tg APP/PS1 mice. The results showed that treatment with atorvastatin significantly reversed the memory deficit in the Tg APP/PS1 mice in a novel object recognition and the Morris water maze tests. Moreover, atorvastatin significantly attenuated Aß1-42 accumulation and phosphorylation of tau (Ser396) in the hippocampus and prefrontal cortex of Tg APP/PS1 mice. In addition, atorvastatin treatment also increased phosphorylation of AKT, inhibited GSK3ß activity by increasing phosphorylation of GSK3ß (Ser9) and decreasing the beta-site APP cleaving enzyme 1 (BACE1) expression. These results indicated that the memory ameliorating effect of atorvastatin may be, in part, by regulation the AKT/GSK3ß signaling which may contribute to down-regulation of Aß1-42 and tau hyperphosphorylation.
