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Proteomics is the study of global gene expression of an organ, body system, fluid, or cellular compartment at the protein level. Proteomic findings are reflective of complex gene × environment interactions, and the importance of this is increasingly appreciated in schizophrenia research. In this review, we outline the main proteomic methods available to researchers in this area and summarize, for the first time, the findings of the main quantitative neuroproteomic investigations of schizophrenia brain. Our review of these data revealed 16 gray matter proteins, and eight white matter proteins that were differentially expressed in the same direction in two or more investigations. Pathway analysis identified cellular assembly and organization as particularly disrupted in both gray and white matter, whereas the glycolysis-gluconeogenesis pathway was the major signaling pathway significantly altered in both. Reassuringly, these findings show remarkable convergence with functional pathways and positional candidate genes implicated from genomic studies. The specificity of schizophrenia proteomic findings are also addressed in the context of neuroproteomic investigations of neurodegenerative disorders and bipolar disorder. Finally, we discuss the major challenges in the field of neuroproteomics, such as the need for high throughput validation methods and optimal sample preparation. Future directions in the neuroproteomics of schizophrenia, including the use of blood-based biomarker work, the need to focus on subproteomes, and the increasing use of mass spectrometry-based methods are all discussed. This area of research is still in its infancy and offers huge potential to our understanding of schizophrenia on a cellular level., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Abnormalities in the size and activity of the insular cortex (IC), a brain region involved in auditory hallucinations and language, have been previously found in brain imaging studies in schizophrenia. In addition, cortical layer 2 has been shown to be abnormal in many brain regions in schizophrenia. In this study, 2-D DIGE was used to quantitatively analyse protein expression in schizophrenia and control cases (n = 15/group) in microdissected layer 2 IC tissue. Proteomic analyses revealed 57 significantly differentially expressed (p<0.05) protein spots in schizophrenia. Validation of differential expression of two of the proteins differentially expressed was subsequently confirmed using Western blotting. This work provides evidence of abnormal protein expression in layer 2 of the IC in schizophrenia, supporting previous work of reduced neuronal size in this cortical layer in the IC. Over half of proteins abnormally expressed in this study have not been reported previously in proteomic studies investigating schizophrenia or neurodegenerative disorders. Proteins found to be abnormally expressed appear to collectively impact on neuronal plasticity through roles in neurite outgrowth, cellular morphogenesis and synaptic function.

There is evidence for both similarity and distinction in the presentation and molecular characterization of schizophrenia and bipolar disorder. In this study, we characterized protein abnormalities in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder using two-dimensional gel electrophoresis. Tissue samples were obtained from 35 individuals with schizophrenia, 35 with bipolar disorder and 35 controls. Eleven protein spots in schizophrenia and 48 in bipolar disorder were found to be differentially expressed (P<0.01) in comparison to controls, with 7 additional spots found to be altered in both diseases. Using mass spectrometry, 15 schizophrenia-associated proteins and 51 bipolar disorder-associated proteins were identified. The functional groups most affected included synaptic proteins (7 of the 15) in schizophrenia and metabolic or mitochondrial-associated proteins (25 of the 51) in bipolar disorder. Six of seven synaptic-associated proteins abnormally expressed in bipolar disorder were isoforms of the septin family, while two septin protein spots were also significantly differentially expressed in schizophrenia. This finding represented the largest number of abnormalities from one protein family. All septin protein spots were upregulated in disease in comparison to controls. This study provides further characterization of the synaptic pathology present in schizophrenia and of the metabolic dysfunction observed in bipolar disorder. In addition, our study has provided strong evidence implicating the septin protein family of proteins in psychiatric disorders for the first time.

The insular cortex is a paralimbic area of the brain thought to have important roles in sensory integration, auditory hallucinations and language. Both structural and functional MRI studies have revealed that this brain area is abnormal in both size and activity in schizophrenia. Further investigation of this region at the cellular level in schizophrenia has not been carried out. In the current study, we conducted a stereological examination of neuronal and glial size and density in layers 2 and 3 of the dorso-caudal region of the insular cortex in 15 schizophrenic, 15 bipolar, 15 unipolar and 15 control patients. These cortical layers are candidate layers based on previous cytoarchitectual investigations. Statistical analysis (ANCOVA, correcting for pH, post-mortem interval and age) showed decreased neuronal volume in layer 2 in schizophrenia (p=0.0008, 16.2% mean reduction). No other significant changes were observed. This study thus provides the first evidence of cytoarchitectural abnormality of the insular cortex in the pathophysiology of schizophrenia but not mood disorders. Further work is needed to investigate the molecular basis for this neuronal abnormality in schizophrenia in order to elucidate its role in the pathophysiology of schizophrenia.

Abnormalities of the anterior cingulate cortex have previously been described in schizophrenia, major depressive disorder and bipolar disorder. In this study 2-DE was performed followed by mass spectrometric sequencing to identify disease-specific protein changes within the anterior cingulate cortex in these psychiatric disorders. The 2-DE system comprised IPGs 4-7 and 6-9 in the first, IEF dimension and SDS-PAGE in the second dimension. Resultant protein spots were compared between control and disease groups. Statistical analysis indicated that 35 spots were differentially expressed in one or more groups. Proteins comprising 26 of these spots were identified by mass spectroscopy. These represented 19 distinct proteins; aconitate hydratase, malate dehydrogenase, fructose bisphosphate aldolase A, ATP synthase, succinyl CoA ketoacid transferase, carbonic anhydrase, alpha- and beta-tubulin, dihydropyrimidinase-related protein-1 and -2, neuronal protein 25, trypsin precursor, glutamate dehydrogenase, glutamine synthetase, sorcin, vacuolar ATPase, creatine kinase, albumin and guanine nucleotide binding protein beta subunit. All but three of these proteins have previously been associated with the major psychiatric disorders. These findings provide support for the view that cytoskeletal and mitochondrial dysfunction are important components of the neuropathology of the major psychiatric disorders.