Exploring lithium’s transcriptional mechanisms of action in bipolar disorder: a multi-step study

Abstract

Lithium has been the first-line treatment for bipolar disorder (BD) for more than six decades. Although the molecular effects of lithium have been studied extensively and gene expression changes are generally believed to be involved, the specific mechanisms of action that mediate mood regulation are still not known. In this study, a multi-step approach was used to explore the transcriptional changes that may underlie lithium's therapeutic efficacy. First, we identified genes that are associated both with lithium exposure and with BD, and second, we performed differential expression analysis of these genes in brain tissue samples from BD patients (n = 42) and healthy controls (n = 42). To identify genes that are regulated by lithium exposure, we used highsensitivity RNA-sequencing of corpus callosum (CC) tissue samples from lithium-treated (n = 8) and non-treated (n = 9) rats. We found that lithium exposure significantly affected 1108 genes (FDR < 0.05), 702 up-regulated and 406 down-regulated. These genes were mostly enriched for molecular functions related to signal transduction, including well-established lithium-related pathways such as mTOR and Wnt signaling. To identify genes with differential expression in BD, we performed expression quantitative trait loci (eQTL) analysis on BD-associated genetic variants from the most recent genome-wide association study (GWAS) using three different gene expression databases. We found 307 unique eQTL genes regulated by BD-associated variants, of which 12 were also significantly modulated by lithium treatment in rats. Two of these showed differential expression in the CC of BD cases: RPS23 was significantly down-regulated (p = 0.0036, fc = 0.80), while GRIN2A showed suggestive evidence of down-regulation in BD (p = 0.056, fc = 0.65). Crucially, GRIN2A was also significantly up-regulated by lithium in the rat brains (p = 2.2e-5, fc = 1.6), which suggests that modulation of GRIN2A expression may be a part of the therapeutic effect of the drug. These results indicate that the recent upsurge in research on this central component of the glutamatergic system, as a target of novel therapeutic agents for affective disorders, is warranted and should be intensified.

Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders

“…Interestingly, long-term treatment with Li and VPA was found to protect against methamphetamine-induced mitochondrial dysfunction and toxicity in animal models [ 14 ] and enhance cell respiration rate in a neuroblastoma cell line, as determined by measurements of mitochondrial membrane potential and mitochondrial oxidation [ 15 ]. At the transcriptional level, the molecular effects of mood stabilizers, Li in particular, have been studied in different experimental models, including animal models [ 16 ], neuroblastoma cells [ 17 ], neurons [ 18 ] and peripheral lymphoblastoid cell lines derived from BD patients [ 19 ]. These studies have demonstrated widespread effects on diverse cellular signaling pathways related to apoptosis, immune functions, protein processing and response to endoplasmic reticulum stress [ 19 ].…”

Effects of chronic lithium treatment on anxious behaviors and serotonergic genes expression in the midbrain raphe nuclei in defeated male mice

“…These results may be useful for understanding the mechanisms of psychotropic LiCl action through the increase of serotonergic gene expression and thereby serotonergic activity. However, it’s necessary to take into consideration that numerous genes associated both with lithium exposure and bipolar disorder were also identified [36–39, 41], and differential expression of these genes in brain tissue samples from patients and healthy controls was studied [63]: lithium exposure significantly affected 1108 genes, 702 of which were upregulated and 406 genes were downregulated. Our neurogenomic data, obtained in last years by whole transcriptomic analysis, revealed changes in the expression of mitochondrial [64], ribosomal [65, 66], monoaminergic [67–70], autistic [71] genes as well as changes in the expression of neurotrophic, transcription factors [72, 73] and collagen [74] genes specific for brain regions in mice with mixed anxiety/depression-like state.…”

rs1990622 variant associates with Alzheimer’s disease and regulates TMEM106B expression in human brain tissues

“…Take TREM2 for example, its expression is upregulated in multiple pathological conditions such as Parkinson’s disease, amyotrophic lateral sclerosis, stroke, traumatic brain injury, and AD, compared with normal controls [ 37 ]. Until now, most eQTLs studies focusing genetic variants associated with neurological diseases were conducted in neuropathologically normal individuals, such as AD (UKBEC [ 38 ], and GSE15745 [ 38 ], and 128 normal subjects [ 39 ]), progressive supranuclear palsy (387 normal subjects) [ 40 ], schizophrenia (UKBEC [ 41 ], GTEx [ 41 ], 128 normal subjects [ 39 ], and 120 normal subjects [ 42 ]), Parkinson’s disease (128 normal subjects [ 39 ], GTEx [ 43 ]), and bipolar disorder (120 normal subjects [ 42 ], GTEx [ 44 ], and UKBEC [ 44 ]). Meanwhile, other eQTLs studies using both AD and other controls were also reported by adjusting for disease status and some critical covariates [ 45 , 46 ].…”