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 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.