Neuronal alterations in AKT isotype expression in schizophrenia

• Published in: Molecular psychiatry Vol. 30; no. 4; pp. 1573 - 1584
• Main Authors: Devine, Emily A., Imami, Ali S., Eby, Hunter, Sahay, Smita, Hamoud, Abdul-rizaq, Golchin, Hasti, Ryan, William, Shedroff, Elizabeth A., Arvay, Taylen, Joyce, Alex W., Asah, Sophie M., Walss-Bass, Consuelo, O’Donovan, Sinead, McCullumsmith, Robert E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2025; Nature Publishing Group
• Subjects: 631/378; 692/699/476/1799; 82/79; Adult; AKT protein; AKT1 protein; Antipsychotics; Behavioral Sciences; Biological Psychology; Brain - metabolism; Female; Forkhead Box Protein O1 - metabolism; FOXO1 protein; Gene expression; Glucose metabolism; Humans; Insulin; Insulin - metabolism; Male; Medicine; Medicine & Public Health; Mental disorders; Middle Aged; Neurons - metabolism; Neurosciences; Pharmacotherapy; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Psychiatry; RNA, Messenger - metabolism; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Signal transduction; Signal Transduction - physiology
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-024-02770-8

Schizophrenia is characterized by substantial alterations in brain function, and previous studies suggest insulin signaling pathways, particularly involving AKT, are implicated in the pathophysiology of the disorder. This study demonstrates elevated mRNA expression of AKT1-3 in neurons from schizophrenia subjects, contrary to unchanged or diminished total AKT protein expression reported in previous postmortem studies, suggesting a potential decoupling of transcript and protein levels. Sex-specific differential AKT activity was observed, indicating divergent roles in males and females with schizophrenia. Alongside AKT, upregulation of PDPK1, a critical component of the insulin signaling pathway, and several protein phosphatases known to regulate AKT were detected. Moreover, enhanced expression of the transcription factor FOXO1, a regulator of glucose metabolism, hints at possible compensatory mechanisms related to insulin signaling dysregulation. Findings were largely independent of antipsychotic medication use, suggesting inherent alterations in schizophrenia. These results highlight the significance of AKT and related signaling pathways in schizophrenia, proposing that these changes might represent a compensatory response to a primary defect of canonical insulin signaling pathways. This research underscores the need for a detailed understanding of these signaling pathways for the development of effective therapeutic strategies.