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.

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder

“…For instance, a genetic variation at the AKAP13 gene, whose levels were increased by lithium in our experiment, has been previously associated with the efficacy of acute haloperidol treatment (Drago et al, 2013). Moreover, a positive correlation between AKT1 gene expression after lithium treatment and an improvement of depressive symptoms has been reported in BD patients (Machado-Vieira et al, 2015). Of note, previous findings have also linked BD with genetic variants of the AKT1 gene (Karege et al, 2012), and AKT1 expression levels have been shown to be increased in BD patients compared to controls (Gouvea et al, 2016).…”

Molecular network of neuronal autophagy in the pathophysiology and treatment of depression

“…Decreased AKT1/mTOR mRNA expression has been reported in short-term bipolar disorder [48] . A recent study showed that neuronal stimulation induces NMDARdependent autophagy through the PI3K-Akt-mTOR pathway in a cellular model of LTD [25] .…”

Lithium protects against methamphetamine-induced neurotoxicity in PC12 cells via Akt/GSK3β/mTOR pathway

“…Evidences also suggest Li can activate Akt, thus indirectly inhibit GSK3 [18,19,20]. Moreover, short-term bipolar disorder leads to the decrease of mRNA expression of Akt/mTOR pathway [21] and Li treatment activates mTOR in renal collecting duct cells [22]. Additionally, Li attenuates MA induced locomotor sensitization through the inhibition of GSK3β [23].…”