The Neurobiology of Bipolar Disorder: Focus on Signal Transduction Pathways and the Regulation of Gene Expression

Bezchlibnyk, Yarema B.; Young, L. Trevor

doi:10.1177/070674370204700203

Cited by 68 publications

(57 citation statements)

References 158 publications

(142 reference statements)

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“…The a1 receptors have also been found to activate other signal transduction systems, such as the mitogen activated protein kinase and cAMP pathways (Michelotti et al, 2000;Piascik and Perez, 2001). Much research has demonstrated that lithium treatment affected cAMP pathways (Bezchlibnyk and Young, 2002). Together with our finding that lithium decreased a1B-AR expression, this suggests that the a1B-AR coupled signaling may be a pathway with multiple targets for lithium.…”

Section: Discussionsupporting

confidence: 76%

“…Prophylactic treatment with lithium prevents recurrences of depression and mania in a substantial proportion of patients with this disorder (Davis et al, 1999). Much research has shown that lithium regulates components of signal transduction pathways and their downstream gene transcription factors, an indication that changes in gene expression are likely to underlie the mechanism of action of the treatment (Manji and Zarate, 2002;Bezchlibnyk and Young, 2002). Lithium-induced changes in gene expression have been documented in both cultured cells and animal models (Kalasapudi et al, 1990;Williams and Jope, 1994;Manji et al, 1995a, b).…”

Section: Introductionmentioning

confidence: 99%

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Identification of Lithium-Regulated Genes in Cultured Lymphoblasts of Lithium Responsive Subjects with Bipolar Disorder

Sun

Young

Wang

et al. 2004

Neuropsychopharmacol

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Lithium, a common drug for the treatment of bipolar disorder (BD), requires chronic administration to prevent recurrences of the illness. The necessity for long-term treatment suggests that changes in genes expression are involved in the mechanism of its action. We studied effects of lithium on gene expression in lymphoblasts from BD patients, all excellent responders to lithium prophylaxis. Gene expression was analyzed using cDNA arrays that included a total of 2400 cDNAs. We found that chronic lithium treatment at a therapeutically relevant concentration decreased the expression of seven genes in lymphoblasts from lithium responders. Five of these candidate lithiumregulated genes, including alpha1B-adrenoceptor (a1B-AR), acetylcholine receptor protein alpha chain precursor (ACHR), cAMPdependent 3 0 ,5 0 -cyclic phosphodiesterase 4D (PDE4D), substance-P receptor (SPR), and ras-related protein RAB7, were verified by Northern blotting analysis in lithium responders. None of these genes were regulated by lithium in healthy control subjects. When we compared the expression of these five genes between bipolar subjects and healthy control subjects at baseline, prior to lithium administration, we found that a1B-AR gene expression was higher in bipolar subjects than in healthy control subjects. Our findings indicate that a1B-AR may play an important role in the mechanism of action of lithium treatment.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Identification of Lithium-Regulated Genes in Cultured Lymphoblasts of Lithium Responsive Subjects with Bipolar Disorder

Sun

Young

Wang

et al. 2004

Neuropsychopharmacol

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“…There have been a number of studies looking at the effects of lithium, an effective prophylactic treatment for BD, on CREB DNA binding, as well as its effects on gene expression. They all concur in that lithium decreases CREB phosphorylation leading to inefficient DNA binding resulting in altered expression of cAMP responsive genes (Bezchlibnyk and Young, 2002). Thus it is possible that genetic variation in genes coding for CREB proteins may help determine response to lithium prophylaxis.…”

Section: Introductionmentioning

confidence: 85%

Lithium response and genetic variation in the CREB family of genes

Mamdani

Alda

Grof

et al. 2008

American J of Med Genetics Pt B

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Bipolar disorder (BD) is a severe psychiatric disorder that affects 1% of the population. Recently, there have been many attempts to identify specific genes that are involved in BD; however, the task of finding susceptibility genes is not easy due to the complexity of the disorder. Since lithium (Li) has been used for over 40 years now as an effective prophylactic agent and response to Li treatment seems to be, at least in part, genetically determined, classification according to Li response is a manner through which more homogeneous populations can be obtained for investigation. It has previously been suggested that Li exerts an effect on signal transduction pathways, such as the cyclic adenosine monophosphate (cAMP) pathway. We carried out an association study of BD with CREB1, CREB2 and CREB3 genes, located at ch 2q32.3-q34, 22q13.1 and 9pter-p22.1, respectively. A total of three promoter single nucleotide polymorphisms (SNP), 14 SNPs in the UTR, 6 exonic and 15 intronic SNPs were investigated for their frequency and haplotype distribution in a BD sample of 180 lithium responders and 69 nonresponders and 127 controls using a SNaPshot multiplex reaction from Applied Biosystems, a modified fluorescent single base pair extension procedure. Following correction for multiple testing, our results suggest that the CREB1-1H SNP (G/A change, p < 0.002) and the CREB1-7H SNP (T/C change, p < 0.002) may be associated with BD and/or lithium response.

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“…Among the multiple cell signal transduction pathways, the cAMP signaling has drawn particular interest (Tardito et al, 2000;Stewart et al, 2001;Bezchlibnyk and Young, 2002), and hyperfunction of cAMP and downstream targets has been postulated for the etiopathology of BAD (Young et al, 1993;Perez et al, 1999). The first cAMP signal target is protein kinase A (PKA), an important phosphorylating enzyme that activates the transcription factors, that is, the cAMP responsive element binding (CREB) protein, and controls the expression of critical genes such as brain-derived neurotrophic factor (BDNF) (Shieh and Ghosh, 1999).…”

Section: Introductionmentioning

confidence: 99%

Drug-Induced Decrease of Protein Kinase A Activity Reveals Alteration in BDNF Expression of Bipolar Affective Disorder

Karege

Schwald

Kouaissi

2004

Neuropsychopharmacol

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Bipolar affective disorder (BAD) is a severe disease whose molecular and cellular bases are not well known. The aim of the present study was to probe the cAMP signaling downstream targets by pharmacologically manipulating the protein kinase A (PKA) enzyme, along with the assessment of brain-derived neurotrophic factor (BDNF) expression in lymphoblasts. The time course of lymphoblast PKA activity (up to 72 h) revealed optimal activity at 24 h. Then, the enzyme activity and protein levels of PKA Ca subunit and phopsho-cAMP responsive element binding (CREB) were assayed in lymphoblasts derived from 12 BAD and 12 control (CT) subjects and cultured for 24 h in the presence of cAMP analog drugs. The results indicated that basal PKA activity and PKA Ca subunit immunolabeling are increased in cells from BAD compared with controls. Enzyme activity was increased by Sp-isomer in BAD and in CT's cells, without change in protein levels. In contrast, the Rp-isomer decreased enzyme activity and protein levels. In drug-naive conditions, there was no change in BDNF expression of BAD cells compared with CT cells. Treatment with Sp-isomer induced increased BDNF in both groups, while treatment with Rp-isomer induced a significant decrease in BDNF expression of BAD compared with CT. The p-CREB changes followed changes in BDNF levels, with increased and decreased Sp-isomer and Rp-isomer treatment, respectively. Our results suggest that mood disorder is associated with PKA upregulation and this could mask alteration in BDNF expression, because slowing down of PKA signaling results in a decrease of BDNF expression. These findings, combined with previous reports, provide a new insight to explain pharmacological features in different diagnostic groups.

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The Neurobiology of Bipolar Disorder: Focus on Signal Transduction Pathways and the Regulation of Gene Expression

Cited by 68 publications

References 158 publications

Identification of Lithium-Regulated Genes in Cultured Lymphoblasts of Lithium Responsive Subjects with Bipolar Disorder

Identification of Lithium-Regulated Genes in Cultured Lymphoblasts of Lithium Responsive Subjects with Bipolar Disorder

Lithium response and genetic variation in the CREB family of genes

Drug-Induced Decrease of Protein Kinase A Activity Reveals Alteration in BDNF Expression of Bipolar Affective Disorder

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