Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):19126-31. doi: 10.1073/pnas.1013032107. Epub 2010 Oct 18.
Recent studies suggest that the human Abelson helper integration site-1 (AHI1) gene on chromosome 6 is associated with susceptibility to schizophrenia and autism, two common neuropsychological disorders with depression symptoms. Mouse Ahi1 protein is abundant in the hypothalamus and amygdala, which are important brain regions for controlling emotion. However, the neuronal function of Ahi1 remains unclear. With the Cre-loxP system, we created a mouse model that selectively reduces Ahi1 expression in neuronal cells. Mice with neuronal Ahi1 deficiency show reduced TrkB level in the brain and depressive phenotypes, which can be alleviated by antidepressant drugs or by overexpression of TrkB in the amygdala. Ahi1 deficiency promotes the degradation of endocytic TrkB and reduces TrkB signaling in neuronal cells. Our findings suggest that impaired endocytic sorting and increased degradation of TrkB can induce depression and that this impaired pathway may serve as a previously uncharacterized therapeutic target for depression.
最近的研究表明，人类染色体 6 上的 Abelson 辅助整合位点 1（AHI1）基因与精神分裂症和自闭症易感性有关，这两种常见的神经心理障碍都伴有抑郁症状。小鼠 Ahi1 蛋白在控制情绪的重要脑区——下丘脑和杏仁核中含量丰富。然而，Ahi1 的神经元功能尚不清楚。利用 Cre-loxP 系统，我们构建了一种在神经元细胞中特异性降低 Ahi1 表达的小鼠模型。神经元 Ahi1 缺失的小鼠大脑中 TrkB 水平降低，表现出抑郁表型，抗抑郁药物或在杏仁核中过表达 TrkB 可以缓解这些表型。Ahi1 缺失促进内吞 TrkB 的降解，并减少神经元细胞中 TrkB 的信号转导。我们的研究结果表明，内吞分选受损和 TrkB 降解增加可诱导抑郁，而这条受损通路可能成为一种以前未被表征的抑郁症治疗靶点。
