Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions

Chia Yuan Chang, Yi Wen Chen, Tsu Wei Wang, Wen Sung Lai*

*此作品的通信作者

研究成果: 雜誌貢獻期刊論文同行評審

8 引文 斯高帕斯(Scopus)

摘要

Accumulating evidence implies that both AKT1 and GABA A receptor (GABA A R) subunit genes are involved in schizophrenia pathogenesis. Activated Akt promotes GABAergic neuron differentiation and increases GABA A R expression on the plasma membrane. To elucidate the role of Akt1 in modulating GABAergic functions and schizophrenia-related cognitive deficits, a set of 6 in vitro and in vivo experiments was conducted. First, an Akt1/2 inhibitor was applied to evaluate its effect on GABAergic neuron-like cell formation from P19 cells. Inhibiting Akt resulted in a reduction in parvalbumin-positive neuron-like cells. In Akt1-/- and wild-type mice, seizures induced using pentylenetetrazol (a GABA A R antagonist) were measured, and GABA A R expression and GABAergic interneuron abundance in the brain were examined. Female Akt1-/- mice, but not male Akt1-/- mice, exhibited less pentylenetetrazol-induced convulsive activity than their corresponding wild-type controls. Reduced parvalbumin-positive interneuron abundance and GABA A R subunit expression, especially in the hippocampus, were also observed in female Akt1-/- mice compared to female wild-type mice. Neuromorphometric analyses revealed significantly reduced neurite complexity in hippocampal pyramidal neurons. Additionally, female Akt1-/- mice displayed increased hippocampal oscillation power and impaired spatial memory compared to female wild-type mice. Our findings suggest that Akt1 deficiency modulates GABAergic interneurons and GABA A R expression, contributing to hippocampus-dependent cognitive functional impairment.

原文英語
文章編號33095
期刊Scientific Reports
6
DOIs
出版狀態已發佈 - 2016 九月 12

ASJC Scopus subject areas

  • 多學科

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