Low doses of lithium and gene ontology analysis: Different action of dose response in neurons

Abstract

AbstractBackgroundThe pharmacological mechanisms of lithium are not completely understood, but current evidence suggests the direct involvement of classic pharmacological targets affecting neurotransmission and signal transduction. These include the modulation of cell‐surface receptors, the release of second‐messengers and downstream signaling molecules, and the subsequent effect on the activity of important regulatory systems, with an impact on the release of transcription factors and gene expression. The aim of this work was to analyze the gene ontology of sub therapeutic and therapeutic doses of lithium in the hippocampus and correlate with lithium response and response to the GSK3B pathway.MethodWe made a gene block network, called “GSKome” and a “LITHIome”, based on protein‐protein interaction data, to identify genes with direct interaction. For this we used the program STRING (v 10.5) and PathCards (v 4.6). All selected proteins for Rattus norvegicus (microarray from primary culture of hippocampal neurons treated with different lithium doses: 0.02mM, 0.2mM and 2mM) had their nomenclature modified in r v3.6.1 (Bioconductor). In the Gene Ontology (GO) analysis we listed the top 5 FDR (false dicover ratio) of GSKome and LITHIome. ClueGO package (Cytoscape) were used for comparative analysis of the gene ontology (GO) between lithium doses with GSKOma and LITIOma.ResultGSKoma and LITIOma lists were compared with 0.02mM, 0.2mM and 2mM neurons samples. The 0.2mM lithium doses compared with LITIOma presents Biological processes presented the highest number of pathways, 27 in total. The Cell Component presented only the caveoline pathway and in the Molecular Functions four altered pathways. The GO analysis of 0.02mM lithium treated samples compared to GSKOma showed no statistical difference in Biological Processes, Cellular Component and Molecular Functions. The 0.2mM dose of lithium‐treated neurons compared with GSKOma were statistically significant in two of the three GO categories. Biological processes presented three pathways: caveolin (40%), axons (40%) and transcription factor (20%) and Molecular Functions, also with three altered pathways: protein kinase (53.64%) DNA transcription (27.27%) and DNA regulation (19.09%).ConclusionThe lithioma block was related to the ontological pathways of protection in therapeutic and subtherapeutic doses of lithium.