McQuillin A, Rizig M, Gurling HM. A microarray gene expression study of the molecular pharmacology of lithium carbonate on mouse brain mRNA to understand the neurobiology of mood stabilization and treatment of bipolar affective disorder. Pharmacogenet Genomics 17: 605-617
Lithium is the most widely prescribed and effective mood-stabilizing drug used for the treatment of bipolar affective disorder. To understand how lithium produces changes in the brain, we studied brain mRNA from 10 mice after treatment with lithium and compared them with 10 untreated controls.
We used the MAS 5.0, Smudge miner, GC-RMA and FDR-AME packages of software (Bioconductor, Seattle, Washington, USA) to determine gene expression changes using Affymetrix MOE430E 2.0 microarrays after 2 weeks of lithium treatment.
We used both a false discovery rate (FDR-AME) assessment of significance and the Bonferroni method to correct for the possibility of false-positive changes in gene expression among the 39,000 genes present in each array. Our primary method of analysis was to use t-tests on normalized gene expression intensities. By using a Bonferroni correction of P<1.28x10(-6), we found that 121 genes showed significant changes in expression. The three genes with the most changed mRNA expression were alanine-glyoxylate aminotransferase 2-like 1 (Agxt2l1), c-mer proto-oncogene tyrosine kinase (Mertk) and sulfotransferase family 1A phenol-preferring member 1 (Sult1a1). Also among the group of 121 genes with significant changes in gene expression that survived Bonferroni correction () were the genes encoding the Per2 period gene (Per2 P=1.33x10(-8), 2.47-fold change), the metabotropic glutamate receptor (Grm3, P=9.48x10(-7), 0.7-fold change) and secretogranin II (Scg2, P=9.48x10(-7), 1.28-fold change) as well as several myelin-related genes and protein phosphatases. By taking a significance value of P<0.05 without Bonferroni or FDR-AME correction, we identified a total of 4474 genes showing changed mRNA expression in response to lithium. FDR-AME analysis showed that 1027 out of these 4474 genes were significantly changed in expression. Among the mRNAs that were significantly changed with t-tests and FDR-AME were several that had already been implicated in response to lithium such as increased brain-derived neurotrophic factor mRNA ( t-test P=0.0008-0.0005, FDR-AME P=0.0396-0.0393, 1.44-fold change) beta-phosphatidylinositol transfer protein (Pitpnb, t-test P<0.0000, FDR-AME P=0.003, 1.26-fold change) and inositol (myo)-1(or 4)-monophosphatase 1(Impa1, t test P<0.0000, FDR-AME P=0.004, 1.22-fold change). Of interest in relation to the side effect of hypothyroidism, which is caused by long-term lithium treatment was the fact that we observed changes in mRNA expression in five genes related to thyroxine metabolism. These included deiodinase (Dio2 t-test P=0.000003-0.004, FDR-AME P=0.0048-0.061, 1.53-fold change) and thyroid hormone receptor interactor 12 (Trip12, t-test P=0.003, FDR-AME P=0.075, 1.19-fold change). Of relevance to multiple sclerosis was the observed upregulation of the long isoform of myelin basic protein (t-test P=0.00013, FDR-AME P=0.0169). Changes in mRNA expression were found in 45 genes related to phosphatidylinositol metabolism using uncorrected t-tests but only 13 genes after FDR-AME. Thus, our work confirms the considerable previous research implicating this system. Gene ontology analysis showed that lithium significantly affected a cluster of processes associated with nucleotide and nucleoside metabolism. The analysis showed that there were 170 genes expressing RNA described as having ATP-binding or ATPase activity that had changed mRNA expression. The changes found have been discussed in relation to previous experimental work on the pharmacology of lithium.
"Consistent with the lithium-induced increase in ETC complex I activity, it was demonstrated that lithium counteracts behavioral effects of the ETC complex I inhibitor rotenone in preclinical models of depression and mania (Toker et al. 2013). Also, the brain complex I subunits NDUFB9, NDUFAB1, and NDUFS7 expression increased in rodents treated with lithium (McQuillin et al. 2007; Toker et al. 2013). Furthermore, lithium increased prefrontal cortex complex I activity in models of mania (Valvassori et al. 2010). "
[Show abstract][Hide abstract] ABSTRACT: Different lines of evidence suggest that mitochondrial dysfunction may be implicated in bipolar disorder (BD) pathophysiology. Mitochondrial electron transport chain (ETC) is a key target to evaluate mitochondrial function, but its activity has never been assessed in unmedicated BD or during mood episodes. Also, lithium has been shown to increase ETC gene expression/activity in preclinical models and in postmortem brains of BD subjects, but to date, no study has evaluated lithium's direct effects on ETC activity in vivo.
"Several microarray studies were carried out to unravel the pathophysiology of bipolar disorder using different species, tissues, and mood-stabilizer treatment regimens (Chetcuti et al, 2008; Konradi et al, 2004; McQuillin et al, 2007; Sun et al, 2006). Among the reported candidate genes almost none replicated between the studies. "
"The effects of psychotropic drugs on the CC are still unclear, and a recent review suggested that few significant effects of medication are shown in DTI studies (Hafeman et al., 2012). It is suggested that lithium may affected myelin gene expression (McQuillin et al., 2007; Brambilla et al., 2009) and mood stabilizers as well as antidepressants may be associated with neurotrophic effects (Manji et al., 2000; Banasr et al., 2004). In addition, a study reported after six weeks of antipsychotic treatment, drug-naive schizophrenia patients showed a progressive change in white matter FA value but the authors also point out that the underlying progression of illness may affect this result (Wang et al., 2013). "
[Show abstract][Hide abstract] ABSTRACT: Structural magnetic resonance imaging (MRI) studies have provided evidence for corpus callosum (CC) white matter abnormalities in bipolar disorder (BD) and schizophrenia (SZ). These findings include alterations in shape, volume, white matter intensity and structural integrity compared to healthy control populations. Although CC alterations are implicated in both SZ and BD, no study of which we are aware has investigated callosal subregion differences between these two patient populations. We used diffusion tensor imaging (DTI) to assess CC integrity in patients with BD (n=16), SZ (n=19) and healthy controls (HC) (n=24). Fractional anisotropy (FA) of CC subregions was measured using region of interest (ROI) analysis and compared in the three groups. Significant group differences of FA values were revealed in five CC subregions, including the anterior genu, middle genu, posterior genu, posterior body and anterior splenium. FA values of the same subregions were significantly reduced in patients with SZ compared with HC. FA values were also significantly reduced in patients with BD compared to the HC group in the same subregions, excepting the middle genu. No significant difference was found between patient groups in any region. Most of the alterations in CC subregions were present in both the BD and SZ groups. These results imply an overlap in potential pathology, possibly relating to risk factors common to both disorders. The one region that differed between patient groups, the middle genu area, may serve as an illness marker and is perhaps involved in the different cognitive impairments observed in BD and SZ.
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