Akting up in the GABA hypothesis of schizophrenia: Akt1 deficiency modulates GABAergic functions and hippocampus-dependent functions.
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.
Department of Psychology, National Taiwan University, Taipei, Taiwan.
Chia-Yuan
CY
Chang
Department of Psychology, National Taiwan University, Taipei, Taiwan.
Yi-Wen
YW
Chen
Department of Life Science, National Taiwan Normal University, Taipei, Taiwan.
Tsu-Wei
TW
Wang
Department of Psychology, National Taiwan University, Taipei, Taiwan.|Graduate Institute of Brain and Mind Sciences, National Taiwan University, Taipei, Taiwan.|Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan.
Wen-Sung
WS
Lai
D000818:Animals; D058256:Brain Waves; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D003292:Convulsants / Q000008:administration & dosage; D005260:Female; D018756:GABA Antagonists / Q000008:administration & dosage; D059330:GABAergic Neurons / Q000378:metabolism / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D007395:Interneurons / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D018345:Mice, Knockout; D010320:Parvalbumins / Q000378:metabolism; D010433:Pentylenetetrazole / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017966:Pyramidal Cells / Q000473:pathology; D011963:Receptors, GABA-A / Q000378:metabolism / Q000502:physiology*; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D012640:Seizures / Q000139:chemically induced
D003292:Convulsants; D018756:GABA Antagonists; D010320:Parvalbumins; D011963:Receptors, GABA-A; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D010433:Pentylenetetrazole