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Predicted Cellular and Molecular Actions of Lithium in the Treatment of Bipolar Disorder: An In Silico Study

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Abstract

Background

Lithium remains the first-line treatment for bipolar disorder (BD), but patients respond to it variably. While a myriad of studies have attributed many genes and signaling pathways to lithium responsiveness, a comprehensive study with an integrated conclusion is still lacking.

Objective

We aim to present an integrated mechanism for the therapeutic actions of lithium in BD.

Methods

First, a list of lithium responsiveness-associated genes (LRAGs) was collected by searching in the literature. Thereafter, gene set enrichment analysis together with gene–gene interaction network analysis was performed, in order to find the cellular and molecular events related to the LRAGs.

Results

Gene set enrichment analyses showed that the chromosomal regions 3p26, 4p21, 5q34 and 7p13 could be novel associated loci for lithium responsiveness in BD. Also, expression pattern analysis of the LRAGs showed their enrichment in adulthood stages and different cell lineages of brain, blood and immune system. Most of the LRAGs exhibited enriched expression in central parts of human brain, suggesting major contribution of these parts in lithium responsiveness. Beside the prediction of several biological processes and signaling pathways related to lithium responsiveness, an interaction network between these processes was constructed that was found to be regulated by a set of microRNAs. Proteins of the network were mainly classified as transcription factors and kinases, which also highlighted the crucial role of glycogen synthase kinase 3β (GSK3β) in lithium responsiveness.

Conclusions

The predicted cellular and molecular events in this study could be considered as mechanisms and also determinants of lithium responsiveness in BD.

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Acknowledgements

The authors thank the Allen Institute for Brain Science (551 North 34th Street, Seattle, Washington 98103, USA) and the Broad Institute (415 Main Street, Cambridge, Massachusetts 02142, USA) for their valuable data, which are publicly available for analyses. The authors also thank Bahman Razi (PhD candidate in Hematology, Department of Hematology and Blood Transfusion, Faculty of Medicine, Tarbiat Modares University, Tehran, Iran) for his kind scientific comments on the manuscript.

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Authors and Affiliations

  1. Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, P.O. Box 14115-154, Tehran, Iran

    Hadi Najafi & Majid Sadeghizadeh

  2. Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran

    Mehdi Totonchi

  3. Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran

    Mehdi Totonchi

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  1. Hadi Najafi
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Correspondence to Majid Sadeghizadeh.

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Electronic supplementary material

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40263_2020_723_MOESM1_ESM.xlsx

Supplemental file S1. The list of the lithium responsiveness-associated genes (LRAGs), collected from previously published articles. These genes are listed by their official symbols and also by their full names (XLSX 17 kb)

40263_2020_723_MOESM2_ESM.xlsx

Supplemental file S2. A subset of LRAGs that were specifically enriched in four signaling pathways. These genes were used as the input data of PANTHER analysis of protein classes. LRAGs lithium responsiveness-associated genes, PANTHER Protein ANalysis THrough Evolutionary Relationships (XLSX 10 kb)

40263_2020_723_MOESM3_ESM.pdf

Supplemental figure S1. Circadian rhythm signaling pathway (KEGG number: map04710). The first-ranked enriched signaling pathway for the LRAGs was circadian rhythm pathway. It consists of cell-autonomous transcription-translation feedback loops that drives rhythmic expression patterns of core clock components. The first negative feedback loop is a rhythmic transcription of period (Per) genes and chryptochrome (Cry) genes. Per and Cry proteins form a heterodimer, which acts on the Clock/Bmal1 heterodimer to repress its own transcription. Per and Cry proteins are phosphorylated by casein kinase epsilon (CkIε), which leads to degradation and restarting of the cycle. The second loop is a positive feedback loop, driven by the Clock/Bmal1 heterodimer, which initiates transcription of target genes containing E-box cis-regulatory enhancer sequences. The components with the red stars denote LRAGs. KEGG Kyoto Encyclopedia of Genes and Genomes, LRAGs lithium responsiveness-associated genes (PDF 1056 kb)

40263_2020_723_MOESM4_ESM.pdf

Supplemental figure S2. Synaptic signaling pathways and their LRAGs. (a) Signaling by a dopaminergic synapse (KEGG number: map04728). (b) Signaling by a cholinergic synapse (KEGG number: map04725). In both pathways, signaling events are shared between neuronal (bottom left and bottom right cells) and glial cells (top). A significant number of LRAGs were enriched for these pathways (denoted as red asterisks). KEGG Kyoto Encyclopedia of Genes and Genomes, LRAGs lithium responsiveness-associated genes (PDF 1922 kb)

40263_2020_723_MOESM5_ESM.pdf

Supplemental figure S3. The signaling pathway of morphine addiction (KEGG number: map05032). The interactions between components of this pathway conditions are illustrated in five different conditions: (a) in the absence of morphine (control). (b) Acute use of morphine. (c) Chronic use of morphine. (d) Withdrawal from chronic use of morphine. (e) Increased adenosine tone, mediated by morphine withdrawal. Red asterisks denote the LRAGs of the pathway. KEGG Kyoto Encyclopedia of Genes and Genomes, LRAGs lithium responsiveness-associated genes (PDF 2827 kb)

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Najafi, H., Totonchi, M. & Sadeghizadeh, M. Predicted Cellular and Molecular Actions of Lithium in the Treatment of Bipolar Disorder: An In Silico Study. CNS Drugs 34, 521–533 (2020). https://doi.org/10.1007/s40263-020-00723-7

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