Dataset Information

Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder.

ABSTRACT: Strong evidence implicates intracellular signaling cascades dysfunction in the pathophysiology of Bipolar Disorder (BD). Regulation of AKT/mTOR pathway is a critical signaling pathway in synaptic neurotransmission and plasticity, also modulating cell proliferation and migration. Gene expression of the AKT/mTOR pathway was assessed in 25 BD (DSM-IV-TR criteria) unmedicated depressed individuals at baseline and after 6 weeks of lithium therapy and 31 matched healthy controls. Decreases in blood AKT1 and mTOR mRNA expression, as well as in BAD/BCL-2 expression ratio were observed in short-term BD patients during depressive episodes in comparison to healthy controls. There was no significant change in the expression of AKT1, mTOR, BCL-2, BAD and NDUFA6 after lithium therapy in the total group of BD subjects. However, the changes in AKT1 expression after lithium treatment were positively correlated with depression improvement. An integrated activity within this pathway was observed at both baseline and post-treatment. The present results support an integrated AKT/mTOR signaling pathway activity in a similar fashion to the described in previous human postmortem and rodents brain studies. Overall, the results reinforce a role for AKT1 and mTOR in the pathophysiology of BD and support the relevance of blood mRNA expression as a valid surrogate biological source to study brain intracellular signaling cascades changes and convergent molecular pathways in psychiatric disorders.

SUBMITTER: Machado-Vieira R

PROVIDER: S-EPMC5863235 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder.

Machado-Vieira Rodrigo R Zanetti Marcus V MV Teixeira Antonio L AL Uno Miyuki M Valiengo Leandro L LL Soeiro-de-Souza Marcio G MG Oba-Shinjo Sueli M SM de Sousa Rafael T RT Zarate Carlos A CA Gattaz Wagner F WF Marie Suely K N SK

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 20150216 4

Strong evidence implicates intracellular signaling cascades dysfunction in the pathophysiology of Bipolar Disorder (BD). Regulation of AKT/mTOR pathway is a critical signaling pathway in synaptic neurotransmission and plasticity, also modulating cell proliferation and migration. Gene expression of the AKT/mTOR pathway was assessed in 25 BD (DSM-IV-TR criteria) unmedicated depressed individuals at baseline and after 6 weeks of lithium therapy and 31 matched healthy controls. Decreases in blood AK ...[more]

PMID: 25726893

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Project description:Bipolar disorder (BPD) is a severe mental illness characterized by episodes of depression and mania. To investigate the molecular mechanisms underlying the pathophysiology of bipolar disorder, we performed transcriptome studies using RNA-seq data from the prefrontal cortex (PFC) of individuals with BPD and matched controls, as well as data from cell culture and animal model studies. We found 879 differentially expressed genes that were also replicated in an independent cohort of post-mortem samples. Genes involving the mechanistic target of rapamycine (mTOR) pathway were down-regulated, while genes interrelated with the mTOR pathway such as Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway were up-regulated. Gene co-expression network analyses identified a module related to the mTOR pathway that was up-regulated in BPD and also enriched for markers of endothelial cells. We also found a down-regulated co-expression module enriched for genes involved in mTOR signalling and in mTOR related pathways and enriched with neuronal markers. The mTOR related modules were also replicated in the independent cohort of samples. To investigate whether the expression of the modules related to mTOR signalling pathway could be differentially regulated in different cell types we performed comparative network analyses in experimental models. We found both up-regulated modules in the PFC significantly overlapped with an up-regulated module in the brain endothelial cells from mice treated with lipopolysaccharides (LPS) and mTOR related pathways such as JAK-STAT, PI3K-Akt and ribosome were enriched in the common genes. In addition, the down-regulated module in the PFC significantly overlapped with a down-regulated module from neurons treated with the mTOR inhibitor, Torin1 and mTOR signalling, autophagy, and synaptic vesicle cycles were significantly enriched in the common genes. These results suggest that co-expression networks related to mTOR signalling pathways may be up- or down-regulated in different cell types in the PFC of BPD. These results provide novel insights into the molecular mechanisms underlying the pathophysiology of BPD.

Project description:Objective: Clinically, it is very difficult to distinguish between major depressive disorder (MDD) and bipolar disorder (BD) in the period of depression. Increasing evidence shows that the insula plays an important role in depression. We aimed to compare the resting-state functional connectivity (rsFC) of insular subregions in patients with MDD and BD in depressive episodes (BDD), who had never experienced manic or hypomanic episodes when they were scanned to identify biomarkers for the identification of two diseases. Methods: We recruited 21 BDD patients, 40 MDD patients and 70 healthy controls (HC). Resting-state functional magnetic resonance imaging (rs-fMRI) was performed. BDD patients had never had manic or hypomanic episodes when they were scanned, and the diagnoses were determined by follow-up. We divided the insula into three parts including the ventral anterior insular cortex (v-AIN), dorsal anterior insular cortex (d-AIN), and posterior insula (PI). The insular-based rsFC was compared among the three groups, and an analysis of the correlation between the rsFC value and Hamilton depression and anxiety scales was carried out. Results: BDD and MDD patients demonstrated decreased rsFC from the v-AIN to the left superior/middle frontal gyrus compared with the HC group. Versus MDD and HC groups, BDD patients exhibited decreased rsFC from the v-AIN to the area in the left orbital frontal gyrus and left superior temporal gyrus (included temporal pole), from the PI to the right lateral postcentral gyrus and from all three insular subregions to the somatosensory and motor cortex. Meanwhile, a correlation between the rsFC value of the PI-right lateral postcentral gyrus and anxiety score was observed in patients. Conclusion: Our findings show BDD and MDD patients have similar decreases in insular connectivity in the dorsal lateral frontal regions, and BDD patients have specific decreased insular connectivity, especially in the somatosensory and motor cortex, which may be used as imaging evidence for clinical identification.

Dataset Information

Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder.

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Decreased AKT1/mTOR pathway mRNA expression in short-term bipolar disorder.

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