Abstract
We have revealed that diacylglycerol kinase η (DGKη)-knockout (KO) mice display bipolar disorder (BPD) remedy-sensitive mania-like behaviors. However, the molecular mechanisms causing the mania-like abnormal behaviors remain unclear. In the present study, microarray analysis was performed to determine global changes in gene expression in the DGKη-KO mouse brain. We found that the DGKη-KO brain had 43 differentially expressed genes and the following five affected biological pathways: “neuroactive ligand-receptor interaction”, “transcription by RNA polymerase II”, “cytosolic calcium ion concentration”, “Jak-STAT signaling pathway” and “ERK1/2 cascade”. Interestingly, mRNA levels of prolactin and growth hormone, which are augmented in BPD patients and model animals, were most strongly increased. Notably, all five biological pathways include at least one gene among prolactin, growth hormone, forkhead box P3, glucagon-like peptide 1 receptor and interleukin 1β, which were previously implicated in BPD. Consistent with the microarray data, phosphorylated ERK1/2 levels were decreased in the DGKη-KO brain. Microarray analysis showed that the expression levels of several glycerolipid metabolism-related genes were also changed. Liquid chromatography-mass spectrometry revealed that several polyunsaturated fatty acid (PUFA)-containing phosphatidic acid (PA) molecular species were significantly decreased as a result of DGKη deficiency, suggesting that the decrease affects PUFA metabolism. Intriguingly, the PUFA-containing lysoPA species were markedly decreased in DGKη-KO mouse blood. Taken together, our study provides not only key broad knowledge to gain novel insights into the underlying mechanisms for the mania-like behaviors but also information for developing BPD diagnostics.
Highlights
Bipolar disorder (BPD) is a mental disorder characterized by unusual shifts in mood from the heights of mania to the depths of depression [1]
The analysis revealed that the deficiency of diacylglycerol kinase η (DGKη) appears to modulate gene expression in five biological pathways including “neuroactive ligand-receptor interaction”, “positive regulation of transcription by RNA polymerase II”, “positive regulation of cytosolic calcium ion concentration”, “Jak-STAT signaling pathway” and “Positive regulation of ERK1 and ERK2 cascade”
To validate the microarray findings, we quantified the expression of two particular genes, Prl and growth hormone (Gh), which were the most upregulated (log2 5.4 ± 1.7 fold, P = 0.031 and log2 5.3 ± 1.8 fold, P = 0.042, respectively) (Table 1), using Reverse transcription polymerase chain reaction (RT-PCR)
Summary
Bipolar disorder (BPD) is a mental disorder characterized by unusual shifts in mood from the heights of mania to the depths of depression [1]. Current reports indicate that the lifetime prevalence of BPD may be closer to 5%. Because of the elevated morbidity and mortality suffered by individuals with BPD, the disorder has been increasingly recognized as a major health problem. 25%–50% of patients with BPD attempt suicide at least once over their lifetimes, and 8%–19% will complete suicide [2]. Despite advances in its diagnosis, the underlying neurobiology of BPD remains largely unknown. Biomarkers for onset and progression, which are essential for precise diagnosis, are presently lacking. BPD is still an unmet medical need
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