Neuronal Abelson helper integration site-1 (Ahi1) deficiency in mice alters TrkB signaling with a depressive phenotype

Abstract

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.neuropathology | neuropsychiatric | neurotrophic | endocytosis | trafficking

Abelson Helper Integration Site-1 Gene Variants on Major Depressive Disorder and Bipolar Disorder

“…Such resilience was exerted by an anxiolytic-like behavioral phenotype, accompanied by a blunted response of the autonomic nervous system and the HPA axis. Another animal model11 also proposed that neuronal AHI1 deficiency may cause a reduced TrkB level in the brain and should bring about depressive phenotypes, which can be alleviated by antidepressant drugs or by overexpression of TrkB in the amygdala. AHI1 deficiency also prompts the degradation of endocytic-TrkB and reduces TrkB signaling in neuronal cells, supporting that increased degradation of TrkB can induce depression and that such impaired pathway may serve as one of putative therapeutic targets for depression 11.…”

“…Another animal model11 also proposed that neuronal AHI1 deficiency may cause a reduced TrkB level in the brain and should bring about depressive phenotypes, which can be alleviated by antidepressant drugs or by overexpression of TrkB in the amygdala. AHI1 deficiency also prompts the degradation of endocytic-TrkB and reduces TrkB signaling in neuronal cells, supporting that increased degradation of TrkB can induce depression and that such impaired pathway may serve as one of putative therapeutic targets for depression 11. Hence, our preliminary findings may add valuable human genetic data for the investigation of the role of AHI1 gene in the development and treatment response for mood disorders in combination with those form previous innovative animal model studies.…”

“…In a recent animal study,11 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. It can be possibly assumed that overexpressed TrkB in the mouse amygdala could ameliorate the depressive phenotype of AHI1 mutant mice since the TrkB signaling plays a critical role in the depression associated with neuropsychiatric disorders 11,12,13.…”

The Joubert Syndrome-associated Missense Mutation (V443D) in the Abelson-helper Integration Site 1 (AHI1) Protein Alters Its Localization and Protein-Protein Interactions

“…HAP1 has been proposed as playing a regulatory role in intracellular trafficking and receptor recycling pathways, whereas Ahi1 has been similarly proposed as having a function in mediating receptor endocytosis (11,38). Therefore, defects in intracellular trafficking may be responsible for the Hap1 knock-out JBTS-phenotype, and such mechanisms will need to be explored in the future.…”

Lower Serum Tropomyosin Receptor Kinase B Levels in Patients with Schizophrenia

“…The mechanism underlying the elevated TrkB serum [28,29] The reason why TrkB could be found in serum is unknown. The function of translocon or direct interactions between protein and lipid are a possible mechanism.…”