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

Abstract

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.

Introduction

The complexity of the pathophysiology of schizophrenia and related psychotic disorders raises important questions regarding master regulator mechanisms integrating diverse molecular factors. The phosphoinositide 3′-kinase (PI3K) – protein kinase B (AKT1) – glycogen synthase kinase (GSK)-3β intracellular signaling system is modulated by dopamine, serotonin, glutamate, neuregulin 1 (NRG1), dysbindin, and Disrupted in Schizophrenia-1 (DISC-1), representing a reliable target for antipsychotics and mood stabilizers (Kalkman, 2006; Bellon, 2007; Freyberg et al., 2010, Karam et al., 2010, Kvajo et al., 2010, Beaulieu, 2011). Recently, we found that a genome-wide association identified psychosis risk variant of the CACNA1C gene, encoding the alpha subunit of the L-type voltage-dependent calcium channel, also affects the AKT system (Balog et al., 2010).

Regarding structural brain alterations, the hippocampus may play a critical role in schizophrenia because multiple pathophysiological factors converge on this brain structure (Freedman and Goldowitz, 2010, Heckers and Konradi, 2010, Tamminga et al., 2010, Lodge and Grace, 2011). Tan et al. (2011) reported that a schizophrenia-related polymorphism of the AKT gene is linked to hippocampal structure and function, with an epistasis with functional polymorphisms in Brain Derived Neurotrophic Factor (BDNF) and Catechol-O-Methyltransferase (COMT) genes. Lower serum BDNF concentration correlates with decreased hippocampal volume in first-episode schizophrenia (Rizos et al., 2011). Finally, poor sensory gating, a putative marker of hippocampal dysfunction, is associated with decreased NRG1-induced AKT activation in lymphoblasts of first-episode patients with schizophrenia (Kéri et al., 2010).

NRG1, a candidate susceptibility factor for psychotic disorders, acts on Epidermal Growth Factor receptors (ErbBs) and plays an essential role in neurodevelopment and synaptic plasticity (Harrison and Law, 2006, Mei and Xiong, 2008, Schmitt et al., 2008, Buonanno, 2010). Although genome-wide association studies did not confirm its association with psychotic disorders (O’Donovan et al., 2008, The Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium et al., 2011, gene expression profiles of neurons derived from reprogrammed fibroblasts of schizophrenia patients into human pluripotent stem cells revealed abnormal patterns of NRG1 expression (Brennand et al., 2011). Sei et al. (2007) investigated NRG1-induced migration of lymphoblasts and demonstrated decreased migration in patients with schizophrenia relative to controls. From a genetic point of view, the magnitude of NRG1-induced lymphoblast migration was associated with polymorphisms of the NRG1, COMT, and AKT genes (Sei et al., 2007, Sei et al., 2010), and NRG1 risk polymorphisms are associated with decreased hippocampal volume (Gruber et al., 2008).

One of the master regulator mechanisms responsible for impaired lymphoblast migration may be decreased AKT phosphorylation in patients with schizophrenia (Sei et al., 2007). Decreased AKT phosphorylation in lymphoblasts of patients is also related to diminished suppression of the P50 event-related potential (Kéri et al., 2010), impaired habituation of autonomic arousal, and delusional ideations in non-clinical individuals (Kéri et al., 2011). However, it is not known whether AKT activation is linked to structural alterations of the hippocampus, which is implicated in various intermediate phenotypes and clinical symptoms of schizophrenia (Freedman and Goldowitz, 2010, Heckers and Konradi, 2010, Tamminga et al., 2010, Lodge and Grace, 2011). To answer this question, we measured NRG1-induced activation of intracellular messenger systems in peripheral lymphoblasts of schizophrenia patients and controls, and calculated correlations with volumes of brain structures. In addition to the AKT system, we also investigated NRG1-induced phosphorylation of ERK (extracellular signal-regulated kinase) in order to test the specificity of potential relationship with brain structure (Sei et al., 2007).