Neuronal alterations in AKT isotype expression in schizophrenia

Area of Science:

• Neuroscience
• Molecular Biology
• Endocrinology

Background:

• Schizophrenia is linked to brain function alterations, with insulin signaling pathways, especially AKT, implicated in its pathophysiology.
• Previous studies show mixed results on AKT protein levels in schizophrenia, necessitating further investigation into transcript and protein dynamics.

Approach:

• Examined mRNA and protein expression of AKT1-3 and related insulin signaling components (PDPK1, FOXO1) in neurons from schizophrenia subjects.
• Investigated sex-specific differences in AKT activity and the influence of antipsychotic medication on these alterations.

Key Points:

• Elevated AKT1-3 mRNA expression was observed in schizophrenia neurons, contrasting with unchanged or reduced total AKT protein levels, suggesting transcript-protein decoupling.
• Sex-specific differential AKT activity was detected, highlighting divergent roles in males and females with schizophrenia.
• Upregulation of PDPK1, protein phosphatases, and the transcription factor FOXO1 suggests compensatory mechanisms in response to insulin signaling dysregulation.

Conclusions:

• The findings underscore the critical role of AKT and related insulin signaling pathways in schizophrenia pathophysiology.
• Observed alterations in AKT signaling appear largely independent of antipsychotic medication, suggesting they are inherent to the disorder.
• These changes may represent a compensatory response to a primary defect in canonical insulin signaling pathways, warranting further research for therapeutic development.