Pathogenesis Of Bipolar Disorder Research Articles

Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder.

Several studies have indicated that patients with bipolar disorder (BD) who respond well to lithium prophylaxis constitute a biologically distinct subgroup. Lithium is thought to stabilize mood by acting at the phosphoinositide cycle. We have investigated a polymorphism located in the gene (PLCG1) that codes for a gamma-1 isozyme of phospholipase (PLC), an enzyme that plays an important role in the phosphoinositide second messenger system. A population-based association study and a family-based linkage study were carried out on patients who were considered excellent responders to lithium prophylaxis. Response to lithium was evaluated prospectively with an average follow-up of 14.4 +/- 6.8 years. The PLCG1 polymorphism was investigated in 136 excellent lithium responders and 163 controls. In addition, the segregation of this marker was studied in 32 families ascertained through lithium-responsive bipolar probands. The allele distributions between lithium-responsive bipolar patients and controls were different, with a higher frequency of one of the PLCG1 polymorphisms in patients (chi2 = 8.09; empirical P = 0.033). This polymorphism, however, confers only a small risk (OR = 1.88, CI 1.19-3.00). Linkage studies with the same marker yielded modest support for the involvement of this gene in the pathogenesis of BD when unilineal families were considered (Max LOD = 1.45; empirical P = 0.004), but not in the whole sample. Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance. Whether this polymorphism is implicated in the pathogenesis of BD or in the mechanism of lithium response remains to be determined.

No evidence for expanded polyglutamine sequences in bipolar disorder and schizophrenia.

Several recent studies have suggested that expanded CAG repeats may contribute to the genetic transmission of bipolar disorder and schizophrenia. In all known disorders associated with expanded CAG repeats, the repeat sequence is translated into glutamine. Therefore the simplest hypothesis is that one or more proteins with expanded polyglutamine sequences are involved in the pathogenesis of bipolar disorder and schizophrenia. In order to examine this hypothesis, we have used an antibody against expanded polyglutamine sequences to examine Western blots prepared from lymphoblastoid cell lines of patients with schizophrenia and bipolar disorder. We also examined Western blots prepared from left frontal cortex tissue samples obtained from 11 schizophrenics post mortem. With the exception of the TATA-binding protein (TBP), we did not detect any proteins containing expanded polyglutamine sequences. Our data therefore suggest either that the expanded repeats which are associated with these disorders do not encode polyglutamine, or that they are within genes that are not expressed within the tissues investigated here.

Exclusion of expansion of 50 CAG/CTG trinucleotide repeats in bipolar disorder.

The purpose of this study was to identify the specific expanded CAG/CTG trinucleotide repeat associated with bipolar disorder. The study employed an efficient multistage approach for using a genomic CAG/CTG screening set. The authors found no evidence of expanded repeats at 43 polymorphic autosomal loci and seven X chromosomal loci. Secondary screening was pursued at the only locus that contained a large allele (37 repeats) in the primary screening. No association was found between allele size and diagnostic status. It is highly unlikely that expansions in repeat size at any of the 50 candidate trinucleotide repeat loci examined are responsible for the association between expanded CAG/ CTG repeats and bipolar disorder. However, although the authors prioritized the repeats that were a priori most likely to be involved, the study does not reject the more general hypothesis that expanded CAG/CTG repeats are implicated in the pathogenesis of bipolar disorder.

No association between chromosome-18 markers and lithiumresponsive affective disorders

An allelic association study of excellent responders to lithium was conducted with a candidate gene (G olf, a Gprotein receptor gene) and five other chromosome-18p markers. G olf is of special interest because it maps to a region of chromosome 18 where two independent groups (Berrettini et al., 1994; Stine et al., 1995) have found linkage to bipolar disorder. It has been proposed that G proteins are involved in the pathogenesis of bipolar disorder, and lithium, an effective prophylactic agent, is known to impair G-protein activation. To reduce heterogeneity — a common obstacle to genetic investigation — only patients who showed excellent response to lithium prophylaxis were studied. Fifty-five genetically unrelated excellent responders to lithium prophylaxis were compared with 94 normal subjects of similar ethnic background. The groups did not differ in either allele or genotype frequency for the tested markers. The data do not support the hypothesis that the tested loci confer a major susceptibility for affective disorders.

5HT2 receptor measurement in schizophrenia by PET

The role of immune response dysregulation has been previously noticed in the pathogenesis of bipolar disorder (BD).In the current investigation, we compared expression levels of eight cytokines and a chemokine (CXCL8) in the peripheral blood of BD patients and healthy subjects. All BD patients were in euthymic phase.We found higher expression of IL-1B, IL-10, IFN-G, TNF-a, TGF-B and IL-2 in male patients compared with male controls (ExR=3.44, P<0.0001, ExR=2.54, P<0.0001; ExR=2.39, P<0.0001; ExR=2.74, P<0.0001; ExR=2.32, P<0.0001; ExR=1.87, P = 0.04 respectively). For these cytokines, no significant differences were found between female patients and female controls. While expression of IL-6 was higher in male patients compared with male controls (ExR=2.07, P = 0.006), in female subjects the opposite trend was detected (ExR=0.44, P = 0.02). However, no significant difference was detected between female subjects. Expression levels of IL-17 were not different between patients and controls or between any subgroups of them. We found significant correlations between expression of IFN-G and age at disease onset (R = 0.25, P = 0.04) as well as expression of CXCL8 and both age of patients and age at disease onset (R = 0.26, P = 0.03; R = 0.25, P = 0.04). Moreover, inverse correlation was detected between expression of TNF-a and age in control group (R=-0.34, P = 0.008).Combination of transcript levels of six genes could differentiate BD patients from healthy subjects with diagnostic power of 0.85 (Sensitivity=78%, Specificity=80% and P<0.0001). The current investigation highlights the role of cytokine coding genes in the pathogenesis of BD and potentiates them as diagnostic biomarkers.

Spatial relationships of neuroanatomic landmarks in schizophrenia

Recent findings implicate the calcium-permeable transient receptor potential (TRP) melastatin subtype 2 (TRPM2) and canonical subtype 3 (TRPC3) channels in the pathogenesis of bipolar disorder (BD). As both channels are involved in calcium and oxidative stress signaling, thought to be disrupted in BD, we sought to determine the effects of elevated oxidative stress on their expression and function. Primary rat cortical neurons and astrocytes were treated with oxidative stressors for 1 (acute) and 4 days (chronic). Expression of TRPC3 and TRPM2 were determined by immunoblotting and real-time PCR. Channel functionality was assessed using a TRPC3 activator, 1-oleoyl-2-acetyl-sn-glycerol (OAG), and live cell, ratiometric fluorometry with the calcium sensitive dye, Fura-2. Neurons treated with rotenone (15–30 nM) for 4 days but not 24 h showed significant dose-dependent decreases in TRPC3 mRNA (31%, p<0.001) and protein levels (60%, p<0.001). Similar dose-dependent attenuation of TRPC3-mediated calcium fluxes was demonstrated upon chronic rotenone exposure relative to vehicle controls. In contrast, TRPM2 mRNA but not protein levels increased (47%, p=0.017) after acute and chronic rotenone treatment. Chronic exposure of neurons to paraquat (1–2 µM), an alternate oxidative stressor, similarly decreased TRPC3 expression (mRNA: 41%; protein: 61%). Unlike neurons, rotenone treatment incurred no changes in astrocyte TRPC3 levels. These findings demonstrate that TRPC3 and TRPM2 channel expression and/or function is sensitive to the redox status of rat primary neurons and that these changes are time dependent. This provides a critical mechanistic link between altered oxidative stress markers, dysfunction of these TRP channels and calcium dyshomeostasis in BD.