Hippocampal volume and the AKT signaling system in first-episode schizophrenia

J Psychiatr Res. 2012 Mar;46(3):279-84. doi: 10.1016/j.jpsychires.2011.12.005. Epub 2011 Dec 30.


Objective: The phosphoinositide 3'-kinase (PI3K)--protein kinase B (AKT1)--glycogen synthase kinase (GSK)-3β system is modulated by several factors implicated in the pathophysiology of schizophrenia. Evidence suggests that neuregulin 1 (NRG1) induces decreased AKT phosphorylation in schizophrenia relative to healthy controls, which may be related to dysfunctional neurodevelopment and neuroplasticity. The aim of this study was to investigate the relationship between NRG1--induced AKT phosphorylation and hippocampal volume in schizophrenia.

Methods: Participants were 20 first-episode patients with schizophrenia who did not receive psychotropic medications and 20 matched healthy controls. We measured the phosphorylated AKT--total AKT and phosphorylated ERK (extracellular signal-regulated kinase)--total ERK ratios in peripheral lymphoblasts before and after NRG1 administration. Whole-brain, left, and right hippocampal volumes were quantified using FreeSurfer software.

Results: Patients with schizophrenia displayed decreased AKT but normal ERK ratio compared with controls. Patients also had a reduction in left hippocampal volume. There was no significant difference between patients and controls in whole-brain and right hippocampal volume. Decreased AKT ratio was associated with reduced hippocampal volume. There was no significant relationship between ERK ratio and brain structure.

Conclusion: Activation of the AKT system is specifically associated with hippocampal volume in first-episode schizophrenia, which provides further evidence for the pivotal role of this messenger system in the pathophysiology of psychotic disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Episode of Care
  • Extracellular Signal-Regulated MAP Kinases / metabolism*
  • Female
  • Genetic Predisposition to Disease
  • Hippocampus* / growth & development
  • Hippocampus* / metabolism
  • Hippocampus* / pathology
  • Humans
  • Male
  • Neuregulin-1* / genetics
  • Neuregulin-1* / metabolism
  • Neuronal Plasticity
  • Organ Size
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Schizophrenia* / genetics
  • Schizophrenia* / metabolism
  • Schizophrenia* / pathology
  • Signal Transduction


  • Neuregulin-1
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases