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

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number33095
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 2016 Sep 12

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gamma-Aminobutyric Acid
Hippocampus
Schizophrenia
Interneurons
GABAergic Neurons
Parvalbumins
Pentylenetetrazole
vpr Genes
GABA-A Receptor Antagonists
Pyramidal Cells
Neurites
GABA-A Receptors
Seizures
Cell Membrane
Neurons
Brain

ASJC Scopus subject areas

  • General

Cite this

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.

In: Scientific Reports, Vol. 6, 33095, 12.09.2016.

Research output: Contribution to journalArticle

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