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Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions
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 GABAerg...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018883/ https://www.ncbi.nlm.nih.gov/pubmed/27615800 http://dx.doi.org/10.1038/srep33095 |
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author | Chang, Chia-Yuan Chen, Yi-Wen Wang, Tsu-Wei Lai, Wen-Sung |
author_facet | Chang, Chia-Yuan Chen, Yi-Wen Wang, Tsu-Wei Lai, Wen-Sung |
author_sort | Chang, Chia-Yuan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5018883 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50188832016-09-19 Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions Chang, Chia-Yuan Chen, Yi-Wen Wang, Tsu-Wei Lai, Wen-Sung Sci Rep Article 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. Nature Publishing Group 2016-09-12 /pmc/articles/PMC5018883/ /pubmed/27615800 http://dx.doi.org/10.1038/srep33095 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Chang, Chia-Yuan Chen, Yi-Wen Wang, Tsu-Wei Lai, Wen-Sung Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions |
title | Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions |
title_full | Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions |
title_fullStr | Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions |
title_full_unstemmed | Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions |
title_short | Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions |
title_sort | akting up in the gaba hypothesis of schizophrenia: akt1 deficiency modulates gabaergic functions and hippocampus-dependent functions |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5018883/ https://www.ncbi.nlm.nih.gov/pubmed/27615800 http://dx.doi.org/10.1038/srep33095 |
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