Targeting beta-Catenin in GLAST-Expressing Cells: Impact on Anxiety and Depression-Related Behavior and Hippocampal Proliferation

摘要

beta -catenin (key mediator in the Wnt signaling pathway) contributes to the pathophysiology of mood disorders, associated to neurogenesis and neuroplasticity. Decreased -catenin protein levels have been observed in the hippocampus and prefrontal cortex of depressed subjects. Additionally, the antidepressants exert, at least in part, their neurogenic effects by increasing -catenin levels in the subgranular zone of the hippocampus. To further understand the role of -catenin in depression and anxiety, we generated two conditional transgenic mice in which -catenin was either inactivated or stabilized in cells expressing CreERT under the control of the astrocyte-specific glutamate transporter (GLAST) promoter inducible by tamoxifen, which presents high expression levels on the subgranular zone of the hippocampus. Here, we show that -catenin inactivation in GLAST-expressing cells enhanced anxious/depressive-like responses. These behavioral changes were associated with impaired hippocampal proliferation and markers of immature neurons as doublecortin. On the other hand, -catenin stabilization induced an anxiolytic-like effect in the novelty suppressed feeding test and tended to ameliorate depressive-related behaviors. In these mice, the control over the Wnt/-catenin pathway seems to be tighter as evidenced by the lack of changes in some proliferation markers. Moreover, animals with stabilized -catenin showed resilience to some anxious/depressive manifestations when subjected to the corticosterone model of depression. Our findings demonstrate that -catenin present in GLAST-expressing cells plays a critical role in the development of anxious/depressive-like behaviors and resilience, which parallels its regulatory function on hippocampal proliferation. Further studies need to be done to clarify the importance of these changes in other brain areas also implicated in the neurobiology of anxiety and depressive disorders.