Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype.
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.
Xu
Xingshun
X
Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA.
Yang
Hao
H
Lin
Yung-Feng
YF
Li
Xiang
X
Cape
Austin
A
Ressler
Kerry J
KJ
Li
Shihua
S
Li
Xiao-Jiang
XJ
D033942:Adaptor Proteins, Vesicular Transport; D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D003863:Depression / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D004195:Disease Models, Animal; D004705:Endocytosis / Q000235:genetics; D006801:Humans; D007031:Hypothalamus / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020813:Receptor, trkB
D033942:Adaptor Proteins, Vesicular Transport; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; C465818:Ahi1 protein, mouse; C064371:Ntrk2 protein, mouse; D020813:Receptor, trkB