Abstract
Accumulating evidence implies that both AKT1 and GABAA receptor (GABAAR) subunit genes are involved in schizophrenia pathogenesis. Activated Akt promotes GABAergic neuron differentiation and increases GABAAR 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 GABAAR antagonist) were measured, and GABAAR 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 GABAAR 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 GABAAR expression, contributing to hippocampus-dependent cognitive functional impairment.
Highlights
Schizophrenia is a multifactorial disorder for which there is a strong genetic predisposition, but the exact cause of schizophrenia remains unclear
It is of great interest to investigate how Akt[1] regulates GABA signalling and GABA-related cognitive functions that might contribute to the pathogenesis of schizophrenia and its associated cognitive deficits
Because PTZ-induced seizures were suppressed in female Akt1−/− mice, we examined whether the number of GABAergic interneurons (Experiment 3a) or the GABAA receptor (GABAAR) expression level (Experiment 3b) in the target brain regions was altered in naïve female Akt1−/− mice compared to female
Summary
Schizophrenia is a multifactorial disorder for which there is a strong genetic predisposition, but the exact cause of schizophrenia remains unclear. Distinct sex-specific phenotypes were identified in Akt1-deficient mice[11,12], and the Akt[1] isoform was reported to be involved in the regulation of hippocampal neuroplasticity and cognition[31]; this regulatory activity of Akt[1] might contribute to the pathogenesis of schizophrenia. Given the importance of Akt[1] signalling and GABAergic function in the pathogenesis of schizophrenia and the involvement of Akt[1] in the regulation of hippocampal functions, the primary goal of this study was to evaluate whether Akt[1] deficiency causes any alteration in GABAergic function or hippocampus-related function at multiple levels. Our findings indicated that Akt[1] deficiency modulates the number of GABAergic interneurons, GABAAR expression, and neuronal morphology in the hippocampus These effects of Akt[1] deficiency might contribute to the impairment of neuronal oscillations and of hippocampus-dependent cognitive functions in female Akt1−/− mice
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