Prominent Synaptic and Metabolic Abnormalities

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Table of Contents

Introduction
The data collection process
Main findings
Significance of the study in the wider context of the area of research
References

Introduction

This study was carried out to determine the prominent synaptic and metabolic abnormalities revealed by proteomic analysis of the dorsolateral prefrontal cortex (dIPFC) in the schizophrenia and bipolar disorder (1). The main functions of the dlPFC are captured in the wilful actions, the working memory and in the making of decisions. There is increasing evidence that shows that this area of the brain fails to function in patients suffering from bipolar disorder and schizophrenia (1). Several studies in the schizophrenic patients have focused on the dorsolateral prefrontal cortex. Previously it has been established that abnormalities in the inhibitory interneuron function, neurotransmission, signal transduction and glial cells are responsible for the neurochemical and molecular basis for the cell alterations (2). Several gene and protein profiling studies have been conducted on post-mortem dlPFC tissue from schizophrenic patients. Proteomic techniques have been utilized in order to gain understanding in the situations where the abnormalities at the gene level are not reflected in the protein expression (5). In the findings of several previous studies, it has been shown significant variations at the protein level with varying PMI times (2, 4). It is possible that the post mortem conditions of the brain tissue such as change in pH may be responsible for the findings that indicate modified metabolism and function of the mitochondria (7).

This study was aimed at achieving further characterization of the differential protein expression in the cortical grey matter in the post-mortem brain tissue taken from the dlPFC of 105 patients using a non hypothesis gel-based approach (5).

The data collection process

Samples for the study were obtained from the Stanley collection of brain tissue in form of blocks of grey matter chipped from the superior frontal gyrus (3, 5). The sample was made up of tissues form 105 patients and was grouped as follows: 35 with schizophrenia, 35 who had suffered from bipolar disorder and 35 controls. Patient information regarding the demographic, histological and clinical details of the cases used for analysis of protein expression was recorded in a table (4). Nine samples were later discarded due to technical difficulties in the verification of demographic data and confirmation of the disease states. The remaining brain tissues were dissected, solubilised and then separated using the two-dimensional gel electrophoresis technique. Image analysis to quantitatively evaluate the proteins was conducted using a personal SI laser densitometer (6, 9). After percentage determination of all the marked spots, the data was sent for evaluation. Data analysis mainly focused on detection of proteins that differed in expression between the control group and either the schizophrenia or the bipolar disorder groups (3, 8). The expression of the proteins in the brain was determined using analysis of covariance to take into account all the errors that may arise due to changes in PH, PMI, age differences of the subjects and the storage intervals. The proteins that showed significantly varied characteristics were identified using the liquid chromatography-tandem mass spectrometry (1, 5). A database search was carried out on the resulting spectral data and the results stored. Further studies to determine the septin abnormalities showed that two protein spots increased significantly in expression in both disorders(3). The same protein was also found to be higher in the bipolar disorders in comparison to the control group.

Main findings

A total of 1944 spots across the group of 105 dlPFC were seen using the two dimensional gel electrophoresis technique (2). Subsequent analysis conducted showed that a total of 101 of the gel spots were expressed differently expressed and thus correctd using analyses of covariance. Out of the 101, 35 more were done away with due to difficulties in visual confirmation or were absent in the gel used for protein identification (7). Therefore visual confirmation was carried out for a total of 66 spots of which 11 were in the schizophrenia group, 48 in the bipolar disorder group and further 7 which were found to be abnormally expressed in the two disorders (5). Mass spectrometry analysis identified a total 63 proteins. Forty five of them were found to be considerably linked to the bipolar disorder, 6 were significantly expressed in the two disorders, while 9 showed prominence in the schizophrenia disorder. The identities of the “protein spots, their fold change alteration in volume density on the 2D gel, the theoretical pI and the MW and the peptide matching were done for each protein” and tabulated (7). Functional ontology grouping of the proteins was done according to information derived from existing literature. This helped in the identification of the protein expression abnormality seen in each group and the differences between them (3, 5). Confirmation studies revealed that two out of the six proteins that had differential expression in the two disorders were variants of septin. The investigation done at the transcript level also showed significant abnormality in the expression of up to “1 proteins according to the Stanley Medical Research Institute array database and also at the protein level”(2).

The findings of this study indicate that there is a broad variation in the septin protein cluster in both the bipolar disorder and schizophrenia. The findings also confirm the earlier findings that implicated both metabolic and synaptic pathology in the two disorders. Grouping of the proteins based on their functions showed a distinct disease profile in the two disorders. Out of the 15 proteins that had a considerable differential expression in schizophrenia, 7 were linked to the function of the synapses while 4 were associated with metabolic function (5). A tiny fraction of the proteins were also associated with protein folding, cytoskeleton, synthesis and the development of the brain (9). In the bipolar disease, up to 25 of the 51 protein that showed considerable differential expression had a significant association with metabolic function, 9 of the 51 were associated with cytoskeletal function while 6 of the 51 were linked to the synaptic function (7). The remaining categories were associated with development of the brain, proteolysis, protein synthesis, cell division, protein folding and regulation of the blood. Using the controls for comparison it was established that most of the proteins that had an abnormal expression on the bipolar disease were seen to undergo an upward regulation rather than a downward regulation. The best distinction was achieved by the predominance of metabolic-associated protein changes in the bipolar disorder, and of synaptic-associated protein changes in schizophrenia (3).

The researchers went further to identify the roles of the identified proteins in the synaptic and metabolic dysfunction in schizophrenia and the bipolar disorder (4). Existing literature indicates that there is vast evidence showing that alterations in the expression of several disorders that are linked to the synapses are usually found in schizophrenic patients. Thus the current research findings that linked the abnormally expressed proteins in schizophrenia to synaptic function are consistent with previous research findings. The researchers were also able to extend the literature by “increasing our knowledge of the identity of some of the synaptic proteins that are associated with the disease process” (9). In this study most of the proteins linked to the synaptic function that were abnormal in schizophrenia were seen to increase rather than decrease. However, this increase can be attributed to the number of septin protein changes in the in the schizophrenia disease (6).

The findings of the study also showed evidence of how the septin family of proteins contributes to the both the bipolar disease and schizophrenia. In the study, it was revealed that up to five variants of septin 5 that was present on the two dimensional gels analysed, were considerably high in the bipolar disease, while three were raised in schizophrenia in comparison to the controls (4). The genes of septin 5 proteins are often located on the “chromosomal region 22q11.2, some parts of this region are normally deleted in patients who are diagnosed with velo-cardio-facial syndrome” and who are often found to exhibit higher changes of developing schizophrenia (8, 9). The septin proteins usually function to bind GTP and usually associated with microtubule filaments and actin (2).

Earlier research findings have implicated alterations in metabolism and functions of the mitochondria in schizophrenic cases. The findings of the current study have added a new dimension to this by linking the same condition to the bipolar disorder, and by extension finding it to be more prominent in the bipolar disorder than in schizophrenia (3).

Significance of the study in the wider context of the area of research

This study is of great importance in the wider are of research that aims to establish the underlying molecular mechanisms in schizophrenia and bipolar disease. The two diseases can be identified as the most “prevalent and debilitating psychiatric illnesses” (1). The identification of the genome areas that have the genes that cause the two diseases can play a vital role in the identification of the onset features of the diseases for better management. This particular research has added an important dimension in the understanding of the two conditions by implicating the involvement of the septin family of proteins, something that had not been done before (5). Though the research does not offer conclusive solution to the proteomic understanding of the two diseases, it does add credibility to the long established hypothesis that bipolar disease and schizophrenia do share genetic risk factors (8). The findings of the current research are consistent with previous researches that have carried out association studies and revealed the association of the two disorders. Previously the studies concerning the genetic risk factors in schizophrenia and the bipolar diseases were characterised by data that lacked specificity in regard to multiple mutations and the mutations the different mutations that appear in some series (5). The current paper has managed to bridge much of this uncertainty by linking the underlying protein defects in both the bipolar disease and schizophrenia to synaptic and metabolism functions. This was possible because the current study made use of the largest number of individuals to have ever been used in such studies (8).

The contribution of this study will inevitably contribute to the broader identification and understanding of the susceptibility genes, from protein expression point of view. This will go further to identify the molecular targets for which effective drugs can be formulated to establish new therapeutically approaches in the treatment and management of schizophrenia and bipolar disorder. Vast researches in this area of study have been able to pin point the “specific genes and proteins that are implicated in bipolar disorder and schizophrenia,” but the variants of the genes that are specifically responsible for the disorders are yet to be verified (7, 9). The variations in different subjects in regard to age and other demographics that have been established by this study will form an important aspect of determining the susceptibility of individuals and the treatment of other contra-indications (3). The determination of common protein expression abnormalities in different conditions such as velo-cardio-facial syndrome and schizophrenia can be used as an important tool in the prediction of disease conditions (2). For instance individuals who are diagnosed with the velo-cardio-facial syndrome should be advised to take preventive measures against schizophrenia and by extension the bipolar disorder. The importance linkage between protein expression and the underlying genetic abnormalities in schizophrenia and bipolar disorder, as described by this study will ensure more specificity in drug formulations to prevent side effects that are being witnessed currently. For instance, some antipsychotic drugs that are currently in use have been associated with serious side effects such as dyskinesia (7). Thus the identification of specific molecular targets will prevent such side effects and ensure that patients with schizophrenia and the bipolar conditions are given better treatment and management (4).

References

Broadbelt, K, W Byne and L Jones. Evidence for the decrease in basilar dentrites of pyramidal cells in schizophrenic medial prefrontal cortex. Schizophr 2002; 58:75-81.

Eastwood, SL and P J Harrison. Hippocampal synaptic pathology in the schizophrenia, bipolar disorder and major depression: a study of complexin mRNAs. Mol Psychiatry 2000; 5:435-435.

Fountoulakis, M and R Hardmei. Postmortem changes in the Level of the brain proteins. Exp Neurol 2001; 167: 86-94.

Frith, G and R Dolan. The role of the prefrontal cortex in higher cognitive functions. Brain Res Cogn Brain 1996; 5:175-181.

Hakak, Y, et al. Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia. Proc Natl Acad Sci 2001; 98:4746-4751.

Mirnics, K, et al. Molecular characterization of schizophrenia viewed by microarrayanalysis of gene expression in prefrontal cortex. Neuron 2000; 28:53-57.

Rosoklija, G, et al. Structural abnormalities of the subicular dendrites in subjects with schizophrenia and mood disorder. Arch Gen Psychiatry 2005; 162:1200-1202.

Strakowski, S M, C M Adler and M P DelBello. Volumetric MRI studies of mood disorders: do they distinguish unipolar and bipolar disorder. Bipolar Disord2002; 4:80-88.

Vawter, MP, et al. Microarray analysis of gene expression in the prefrontal cortex in schizophrenia: a preliminary stud. Schizophr Res 2002; 58:11-20.

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Prominent Synaptic and Metabolic Abnormalities

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