Pathophysiology Of Bipolar Illness Research Articles

Region-specific dysregulation of glycogen synthase kinase-3β and β-catenin in the postmortem brains of subjects with bipolar disorder and schizophrenia.

There is both direct and indirect evidence suggesting abnormalities of glycogen synthase kinase (GSK)-3β and β-catenin, two important components of the Wingless-type (Wnt) signaling pathway, in the pathophysiology of bipolar illness and possibly schizophrenia (SZ). In order to further clarify the role of the Wnt signaling pathway in the pathophysiology of bipolar disorder (BP) and SZ, we studied GSK-3β and β-catenin in the postmortem brains of subjects with these disorders. We determined the protein expression of GSK-3β, phosphorylated form at serine 9 position (pGSK-3-ser-9), and β-catenin using the western blot technique, and mRNA using the quantitative polymerase chain reaction (qPCR) method, in the dorsolateral prefrontal cortex (DLPFC), cingulate gyrus (CG), and temporal cortex (TEMP) obtained from 19 subjects with BP, 20 subjects with SZ, and 20 normal control (NC) subjects. We found that the protein expression of GSK-3β, pGSK-3β-ser-9, and β-catenin was significantly decreased in the DLPFC and TEMP, but not in the CG, of subjects with BP compared with NC subjects. The mRNA expression of GSK-3β and β-catenin was significantly decreased in the DLPFC and TEMP, but not in the CG, of subjects with BP compared with NC subjects. There were no significant differences in the protein or mRNA expression of GSK-3β, pGSK-3β-ser-9, or β-catenin between subjects with SZ and NC subjects in any of the brain areas studied. These studies show region-specific abnormalities of both protein and mRNA expression of GSK-3β and β-catenin in postmortem brains of subjects with BP but not subjects with SZ. Thus, abnormalities of the Wnt signaling pathway may be associated with the pathophysiology of bipolar illness.

Up-Regulation of NOTCH4 Gene Expression in Bipolar Disorder: Future Studies

Back to table of contents Previous article Next article Communications and UpdatesFull AccessUp-Regulation of NOTCH4 Gene Expression in Bipolar Disorder: Future StudiesMing Li, Ph.D., and Bing Su, Ph.D.Ming LiSearch for more papers by this author, Ph.D., and Bing SuSearch for more papers by this author, Ph.D.Published Online:1 May 2013https://doi.org/10.1176/appi.ajp.2013.12121529AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: In the December 2012 issue, Dieset et al. (1) reported significant up-regulation of NOTCH4 gene expression in whole blood in patients with bipolar disorder relative to healthy comparison subjects, and they identified several single-nucleotide polymorphisms (SNPs) that were significantly associated with NOTCH4 expression. This is a nice piece of research, and their findings have encouraged future research on the molecular mechanisms of NOTCH4 in bipolar disorder. However, several lines of their study data await further validation.First, we are curious about whether the altered NOTCH4 expression that was observed in patients was caused by changes in the genetic background in bipolar disorder (related to the pathogenesis of the illness) or was just an outcome of the patients' physiological conditions. This is an important issue, but was inconclusive in the article, although the authors conducted the analyses adjusting for a range of confounders. A plausible solution to this problem is the use of an intermediate group: the healthy siblings of patients. These populations shared numerous genetic risk factors with the clinical patients but did not have any psychiatric illnesses. If the NOTCH4 expression was also elevated in the healthy siblings of bipolar patients relative to healthy comparison subjects, we could conclude that up-regulation of NOTCH4 expression may be related to the genetic mechanism in bipolar disorder and is likely involved in the pathophysiology of bipolar illness. However, because such data were absent in the Dieset et al. study, we are cautious about drawing any conclusions before further investigations.Another issue we are concerned with is the analyses of SNPs in or around NOTCH4 and their associations with gene expression. Dieset et al. observed significant effects of the SNPs on NOTCH4 expression only in healthy individuals but not in bipolar patients, although the effect went in the same direction. Are these significantly associated SNPs authentic genetic risk factors for bipolar disorder? We examined their associations with bipolar disorder in the case-control samples of European ancestries published by the Psychiatric GWAS Consortium (2), which are the largest samples so far. However, none of these SNPs were significant (Table 1), suggesting that they are not risk variants for bipolar disorder even if they show strong associations with NOTCH4 expression in healthy individuals. On the other hand, if the increased NOTCH4 expression in patients was related to genetic mechanisms in bipolar disorder, the gene may harbor unidentified SNPs that are significantly associated with up-regulated NOTCH4 expression in patients. We think these SNPs may be the authentic risk genetic variants for bipolar disorder, and we call for future studies.TABLE 1. Association of the NOTCH4 Single-Nucleotide Polymorphisms (SNPs) With Bipolar Disorder in Samples Reported by the Psychiatric GWAS Consortium (7,481 Case Subjects and 8,250 Comparison Subjects)AnalysisSNPPositionAlleleFrequencypOdds RatioSErs51032132302370A0.18850.0771.0550.030rs38970332307217C0.81150.0830.9540.027rs36505332303966G0.19670.0661.0520.028rs40489032306845A0.29510.9530.9990.024rs313492632308125C0.78690.0500.9500.026rs41592932297010C0.28690.7500.9920.026rs926787332307330C0.57380.1960.9690.025TABLE 1. Association of the NOTCH4 Single-Nucleotide Polymorphisms (SNPs) With Bipolar Disorder in Samples Reported by the Psychiatric GWAS Consortium (7,481 Case Subjects and 8,250 Comparison Subjects)Enlarge tableFrom the State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China.The authors report no financial relationships with commercial interests.References1 Dieset I, Djurovic S, Tesli M, Hope S, Mattingsdal M, Michelsen A, Joa I, Larsen TK, Agartz I, Melle I, Røssberg JI, Aukrust P, Andreassen OA, Ueland T: Up-regulation of NOTCH4 gene expression in bipolar disorder. Am J Psychiatry 2012; 169:1292–1300Link, Google Scholar2 Psychiatric GWAS Consortium Bipolar Disorder Working Group: Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011; 43:977–983Crossref, Medline, Google Scholar FiguresReferencesCited byDetailsCited ByNone Volume 170Issue 5 May 2013Pages 560a-561 Metrics PDF download History Accepted 1 January 2013 Published online 1 May 2013 Published in print 1 May 2013

Memantine reduces mania-like symptoms in animal models

Memantine, a selective antagonist of the N-methyl-D-aspartate receptor, is approved for the treatment of moderate to severe Alzheimer's disease. Ion dysregulation is thought to be involved in the pathophysiology of bipolar illness, suggesting that memantine may be effective in treating bipolar manic and/or depressive episodes. We utilized two preclinical models of mania that mimic pathophysiologic changes seen in bipolar illness to examine the potential efficacy of memantine in the treatment of this disorder. Locomotor hyperactivity of male Sprague–Dawley rats in an open field was induced with intracerebroventricular (ICV) administration of 10−3 M ouabain. Memantine (2.5, 5 or 7.5mg/kg), lithium (6.75mEq/kg), or vehicle were administered acutely via intraperitoneal injection immediately prior to ouabain, then chronically for 7days (oral memantine 20, 30, and 40mg/kg/day in water; lithium 2.4g/kg food). In a second model of bipolar disorder, cycling between population spikes and epileptiform bursts was investigated in rat hippocampal slices treated with ouabain (3.3μM) alone or in combination with memantine (0.5, 1.0, and 5.0μM). Ouabain-induced hyperlocomotion was normalized with acute and chronic lithium and chronic use of memantine. Memantine delayed the onset of ouabain-induced-cycling in hippocampal slices. Memantine may have antimanic properties.

Glycogen synthase kinase-3β in the platelets of patients with mood disorders: Effect of treatment

Glycogen synthase kinase (GSK)-3β, an important component of the Wnt signaling pathway, is involved in numerous cellular functions. That GSK-3β may be involved in the pathophysiology of bipolar (BP) illness is based on the observation that lithium, a mood-stabilizing drug, inhibits GSK-3β both in vitro and in vivo. We determined the protein expression of GSK-3β in the cytosol and membrane fractions of the platelets obtained from patients with major depressive disorder (MDD) and BP illness, before treatment and after treatment with antidepressants or mood-stabilizing drugs, respectively. Protein expression was determined using the Western blot technique. We observed that the protein expression of GSK-3β was significantly reduced in the membrane and cytosol fractions of platelets from drug-free patients with BP illness, but not from the drug-free patients with MDD, compared with normal control subjects. Treatment with mood-stabilizing drugs significantly increased the protein expression of GSK-3β in the membrane and cytosol fractions of platelets from BP patients compared with pre-treatment levels, and the post-treatment levels were similar to those observed in normal control subjects. On the other hand, there was no significant effect of treatment with antidepressants on GSK-3β protein expression either in the membrane or in the cytosol fractions of platelets from MDD patients. These results suggest that GSK-3β may play an important role in the pathophysiology of BP illness but not MDD and that its abnormality may be corrected by treatment with mood-stabilizing drugs, suggesting that GSK-3β may be a state rather than a trait marker for BP illness.

A commentary on "Sleep disturbance in bipolar disorder."

Sleep disturbances are among the most common clinical features of bipolar affective disorder and are typically present in manic, hypomanic, mixed, and depressive episodes. The processes that regulate sleep are relevant to the pathophysiology of bipolar illness and further study of these processes may help to elucidate fundamental associations with central nervous system arousal and cerebral metabolism. Among the various therapeutic interventions that are used to treat insomnia associated with bipolar affective disorder, the strategies and approaches of behavioral sleep medicine warrant greater attention.

Behavioural sensitization to repeated sleep deprivation in a mice model of mania

Sensitization to the effect of stress has been hypothesized as a mechanism to explain episode recurrence and cycle acceleration in bipolar disorder. Naturalistic observations and experimental work in human patients suggested that sleep deprivation can trigger manic episodes of illness. In rats sleep deprivation (SD) with the platform method caused mania-like behaviours thus providing an animal model of mania with face, construct, and predictive validity. In the present study we administered SD or control stress to male CD1 mice following a dose–response protocol based on time of exposure to the experimental conditions (6, 12 or 24 h) and repetition of treatment (three times). SD, but not stress-control conditions, increased motor activity and aggressive behaviours. The behavioural activation followed a dose–response curve based on length of treatment, with non-significant trends after 6 h, significant effects after 12 h, and maximal effects after 24 h. Moreover, the behavioural activation followed a time–response curve, with progressive sensitization to the effects of SD, but not of control stress, upon its repetition. This is the first animal model of behavioural sensitization to the effects of a specific stress (sleep deprivation) known to trigger mania in bipolar patients. We expect it to be useful to test the efficacy of antimanic and mood-stabilizer drugs, and to study the neurobiological correlates of manic reactions in order to gain new insight into the pathophysiology of bipolar illness and to identify new targets for treatment.

Decreased protein kinase C (PKC) in platelets of pediatric bipolar patients: Effect of treatment with mood stabilizing drugs

Pediatric bipolar disorder (PBD) is a major public health concern, however, its neurobiology is poorly understood. We, therefore, studied the role of protein kinase C (PKC) in the pathophysiology of bipolar illness. We determined PKC activity and immunolabeling of various PKC isozymes (i.e., PKC α, PKC βI, PKC βII, and PKC δ) in the cytosol and membrane fractions of platelets obtained from PBD patients and normal control subjects. PKC activity and PKC isozymes were also determined after 8 weeks of pharmacotherapy of PBD patients ( n = 16) with mood stabilizers. PKC activity and the protein expression of PKC βI and βII, but not PKC α or PKC δ, were significantly decreased in both membrane as well as cytosol fractions of platelets obtained from medication-free PBD patients compared with normal control subjects. Eight weeks of pharmacotherapy resulted in significantly increased PKC activity but no significant changes in any of the PKC isozymes in PBD patients. These results indicate that decreases of specific PKC isozymes and decreased PKC activity may be associated with the pathophysiology of PBD and that pharmacotherapy with mood stabilizing drugs results in an increase and normalization of PKC activity along with improvement in clinical symptoms.

Digoxin-Like Immunoreactive Factor in Human Cerebrospinal Fluid

Back to table of contents Previous article Next article LETTERFull AccessDigoxin-Like Immunoreactive Factor in Human Cerebrospinal FluidRif S. El-Mallakh M.D.James Miller Ph.D.Roland Valdes Jr., Ph.D.,Tamella Buss Cassis M.D.,Rena Li M.D., Ph.D.,Rif S. El-Mallakh M.D.Search for more papers by this authorJames Miller Ph.D.Search for more papers by this authorRoland Valdes Jr., Ph.D.Search for more papers by this author,Tamella Buss Cassis M.D.Search for more papers by this author,Rena Li M.D., Ph.D.Search for more papers by this author,Published Online:1 Jan 2007AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail SIR: Mammals produce a family of endogenous compounds that resemble the sodium pump-inhibiting cardiac glycosides, digoxin and ouabain. 1 These endogenous cardenolides have been proposed to be important in the pathophysiology of bipolar illness, where it is relatively deficient in the serum of manic subjects. 1 The measurement of these compounds in the CNS has not been previously documented. Refrigerated cerebrospinal fluid (CSF) waste was frozen at −70°C within 18 hours of collection. Digoxin-like immunoreactive factor (DLIF) was measured by radioimmunoassay as described by Grider et al., 1 using components provided by New England Nuclear (Billerica, Mass.). The correlation among four samples quantified twice was 0.88. Ten samples were studied from three women and seven men. Mean age among the women was 41.9 years (range=30 to 53), and among the men it was 61.6 years (range=32 to 94). Mean DLIF concentration was 91.7 pg digoxin equivalents/ml.Comment Human CSF contains a substance which cross reacts with antidigoxin antibodies. This supports previous reports of CSF factors that bear immunologic resemblance to cardiac glycosides 2 and sodium pump inhibitory activity of CSF. 3 Though the source of CSF DLIF is not known, similar compounds have been purified from mammalian hypothalamus. 4 Given that the hypothalamic-pituitary-adrenal axis may be dysregulated in bipolar illness, that DLIF production is responsive to dexamethasone and adreno-corticotropin hormone (ACTH), 5 and that DLIF may be dysregulated in bipolar subjects, 1 it would seem important to study CSF DLIF in bipolar illness. Department of Pathology and Laboratory Medicine, University of Louisville School of Medicine, Louisville, Ky.Advanced Dermatology and Dermaesthetics, Louisville, Ky.Sun Health Institute, Sun City, Ariz.

Neurobiological principles of bipolar affective disorders

The neurobiology of bipolar affective illness can be described in a model with structural and functional components, which also address the role of stressors, coping mechanisms, and psychophysical disposition. More data exist on depressive than on manic patients or on patients switching from one clinical pole to the other. Structural and functional chronobiological alterations appear to play a major role in the pathophysiology of bipolar illness. From an anatomical view, neurobiological abnormalities are primarily confined to limbic-striatal-pallidal-thalamocortical circuits. The whole cascade of neural signaling is changed starting from neurotransmitters and neuromodulators to receptor-mediated intracellular signal transduction targeting nuclear gene expression. Transnosological factors such as suicidal tendency appear to essentially modulate those changes. Replicated data on decisive neurobiological differences between bipolar and unipolar affective disorders are currently not yet available.

Effect of ethacrynic acid on sodium pump alpha isoforms in SH-SY5Y cells.

Ethacrynic acid (ECA), a diuretic that has several cellular actions, increases expression of the sodium and potassium-activated adenosine triphosphatase (Na, K-ATPase or Na pump) in normal lymphocytes, but not in lymphocytes of bipolar patients. While this has been proposed to be important in the pathophysiology of bipolar illness, the response of neural tissues to ECA is unknown. Human neuroblastoma SH-SY5Y cells differentiated with 10-microM retinoic acid were treated with various ECA concentrations for 3 days, and changes in Na-pump alpha-isoform expression were quantified with densitometric analysis of Western bands. Expression of alpha1 and alpha3 Na pump isoforms significantly increased with 10-5 M ECA. Cells treated with 10-6 or 10-7 M ECA showed no change in Na-pump expression, while cells treated with 10-4 M ECA died. The alpha2 isoform could not be detected in differentiated SH-SY5Y cells. The effect of ECA on alpha1-isoform in neural tissue is similar to that observed in lymphocytes. As alpha3 isoform is not expressed in lymphocytes, however, we conclude that lymphocytes are an incomplete model of neural tissue.

Neurobiology of bipolar illness: implications for future study and therapeutics.

Many findings implicating prefrontal cortical and limbic areas of the brain and endocrine systems in the neuropathology and pathophysiology of bipolar illness have greatly increased our understanding of the neurobiology of the illness. New imaging techniques such as PET, MRI, SPECT, and MRS have detailed more evidence of specific regional alterations in the brains of bipolar patients than was thought possible just 20 years ago. These methods are beginning to be used to help predict response to treatment. Examining the mechanisms of action of mood stabilizers (such as lithium, carbamazepine, and valproate) has provided clues to potential underlying neurobiological abnormalities in the illness. Recent studies of postmortem brain tissue have begun to confirm prefrontal cortical and limbic neurochemical and microstructural alterations in patients with bipolar illness compared with controls. It is postulated that it is the balance between primary pathological versus secondary adaptive alterations in gene expression in the illness and their enhancement or dampening by pharmacotherapy, that may determine the episodic course of mood fluctuations and remissions. Further examination of the pathophysiology and neurobiology of bipolar illness should lead to both more effective treatments and, potentially, secondary and even primary episode prevention.

Protein Kinase C and Phospholipase C Activity and Expression of Their Specific Isozymes Is Decreased and Expression of MARCKS Is Increased in Platelets of Bipolar but Not in Unipolar Patients

Phospholipase C (PLC) and protein kinase C (PKC) are important components of the phosphoinositide (PI) signaling system. To examine if the abnormalities observed in the PI signaling system of patients with affective disorders, reported in previous studies, are related to abnormalities in one or more of its components, we studied PKC, PI-PLC activity, the expression of their specific isozymes, and expression of myristoylated alanine-rich C-kinase substrate (MARCKS) in platelets obtained from 15 drug-free hospitalized patients with bipolar disorder and 15 with major depressive disorder (unipolar) and from 15 nonhospitalized normal control subjects. We observed a significant decrease in PI-PLC and PKC activity and the expression of selective PKC α, βI, βII, and PLC δ1 isozymes in membrane and cytosol fraction of platelets from bipolar but not unipolar patients. On the other hand, the level of MARCKS was significantly increased in membrane and cytosol fraction of platelets from patients with bipolar but not unipolar disorders. These results suggest that alterations in PKC, PLC, and MARCKS may be involved in the pathophysiology of bipolar illness.

Ouabain induction of cycling of multiple spike responses in hippocampal slices is delayed by lithium

Alterations in sodium- and potassium-activated adenosine triphosphatase (Na,K-ATPase) activity have been associated with changes of mood states and lithium treatment in bipolar illness. We examined the effects of ouabain and lithium on evoked population responses in rat hippocampal slices. In vitro 3.3 μM ouabain induced cycling between epliptiform activity and unresponsiveness in 18.5% of slices. In vitro ouabain, at 1–10 μM, induced epileptiform multiple spike responses. In vivo lithium pretreatment for 10–21 days produced a significant delay in the onset of this ouabain-induced epileptiform activity compared to control animals. These findings are consistent with other work which suggests that Na,K-ATPase inhibition can both activate and suppress excitable tissues and that lithium pretreatment can mitigate these effects. The implications of these results and others regarding the pathophysiology of bipolar illness are discussed.

Alpha2 isoform of the Na,K-adenosine triphosphatase is reduced in temporal cortex of bipolar individuals

Background: The pathophysiology of bipolar illness has been associated with changes in transmembrane ion flux and redistribution of biologically active ions. The recent identification of multiple isoforms of Na,K-adenosine triphosphatase (ATPase) α and β subunits raises the possibility of altered pump isoform expression. Methods: We determined Na,K-ATPase α subunit expression in postmortem temporal cortex gray matter from individuals suffering from bipolar disorder, schizoaffective disorder, schizophrenia, and matched normal controls. Quantification of isoform expression was accomplished via densitometric scanning of Western blots utilizing isoform-specific antibodies. Results: Bipolar individuals exhibited a significant reduction in the abundance of the α2 isoform of Na,K-ATPase compared to normal controls. Schizophrenic and schizoaffective brains were not significantly different from normal controls. Conclusion: These data suggest that previously observed abnormalities in regulation and distribution of ions in bipolar illness may be related to specific α2 dysregulation.

Lithium prevents ouabain-induced behavioral changes. Toward an animal model for manic depression.

Both mania and bipolar depression have been associated with decrements in the activity of the sodium and potassium-activated adenosine triphosphatase (Na,K-ATPase) membrane pump. Although the role of this observation in the pathophysiology of bipolar illness is unclear, it has been proposed that this defect could be central to the pathogenesis of the illness. In an effort to test this hypothesis, the authors examined the efficacy of lithium pretreatment in attenuating behavioral changes secondary to acute administration of a single intracerebroventricular (i.c.v.) dose of the Na,K-ATPase-inhibiting compound, ouabain, in the Sprague-Dawley rat. Ouabain (10(-3)M) significantly decreased motor activity in automated activity monitors. Lithium pretreatment for 7 d totally prevented this effect. These preliminary data suggest that i.c.v. ouabain administration in the rat may prove to be a viable animal model for bipolar illness.

Is the Na(+)-K(+)-ATPase the link between phosphoinositide metabolism and bipolar disorder?

Recent experimental work suggests involvement of the phosphatidyl inositol second messenger system in the biochemical mechanism of lithium action, but this work has not shed light on the pathophysiology of bipolar illness. Earlier work had established reduction in sodium-potassium-activated adenosine triphosphatase (Na(+)-K(+)-ATPase) activity as a consistent marker of mood in bipolar illness but had only partially illuminated mechanisms of the action of lithium. Now, advances from research in diabetic neuropathy suggest that inositol phosphate and diacylglycerol metabolism are indeed linked to Na(+)-K(+)-ATPase activity. The data are compatible with a model in which a primary decrease in Na(+)-K(+)-ATPase activity in bipolar patients can stimulate an increase in phosphoinositide hydrolysis, thereby generating the equivalent of a second messenger signal in the absence of a first message. Lithium appears to act by blocking this false second message.