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Review
. 2022 Sep 10;23(18):10489.
doi: 10.3390/ijms231810489.

MicroRNAs, Stem Cells in Bipolar Disorder, and Lithium Therapeutic Approach

Donatella Coradduzza  1 , Giuseppe Garroni  1 , Antonella Congiargiu  1 , Francesca Balzano  1 , Sara Cruciani  1 , Stefania Sedda  1 , Alessandra Nivoli  2 , Margherita Maioli  1   3
Affiliations
Review

MicroRNAs, Stem Cells in Bipolar Disorder, and Lithium Therapeutic Approach

Donatella Coradduzza et al. Int J Mol Sci. .

Abstract

Bipolar disorder (BD) is a severe, chronic, and disabling neuropsychiatric disorder characterized by recurrent mood disturbances (mania/hypomania and depression, with or without mixed features) and a constellation of cognitive, psychomotor, autonomic, and endocrine abnormalities. The etiology of BD is multifactorial, including both biological and epigenetic factors. Recently, microRNAs (miRNAs), a class of epigenetic regulators of gene expression playing a central role in brain development and plasticity, have been related to several neuropsychiatric disorders, including BD. Moreover, an alteration in the number/distribution and differentiation potential of neural stem cells has also been described, significantly affecting brain homeostasis and neuroplasticity. This review aimed to evaluate the most reliable scientific evidence on miRNAs as biomarkers for the diagnosis of BD and assess their implications in response to mood stabilizers, such as lithium. Neural stem cell distribution, regulation, and dysfunction in the etiology of BD are also dissected.

Keywords: bipolar disorder (BD); lithium; microRNA; molecular mechanisms; neural stem cells; stem cells.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(1) Circulating MiR-144 in patients without drugs with bipolar disorders is lower than that in healthy individuals. (2) MiRNA-144 levels increase after lithium treatment. (3) Glycogen synthase kinase 3 (GSK-3) is the therapeutic target of lithium for BD treatment. (4) GSK3β is involved in regulating gene expression by phosphorylation and therefore destabilizing MEF2. GSK3β activity in BD represses the MEF2 transactivation properties. GSK3β pharmacological inhibition with lithium causes increased activity of MEF2. (5) MEF2 proteins are recruited to the target GATA promoter. GATA transcription factor and MEF2 induce miR-144/451 transcription.
Figure 2
Figure 2
(1) Circulating MiR-134 in patients with bipolar disorders without drugs is lower than that in healthy individuals; (2) MiRNA-134 levels increase significantly after four weeks of lithium treatment; (3) GSK3β is the therapeutic target of lithium in the treatment of BD. (4) GSK3β is involved in regulating gene expression by phosphorylating and thus destabilizing MEF2. GSK3β activity in BD represses the MEF2 transactivation properties. GSK3β pharmacological inhibition by lithium causes increased activity of MEF2. (5) The MEF2 transcription factor leads to the up-regulation of mir-134 in patients with lithium treatment.
Figure 3
Figure 3
Circulating MiR-34 in patients with bipolar disorder is higher than that in healthy individuals. (2) MiRNA-34 levels decrease after lithium treatment. (3) GSK3β is the therapeutic target of lithium in the treatment of BD. (4) GSK3β is involved in the regulation of gene expression by phosphorylating p53; the pharmacological inhibition of GSK3β with lithium counteracts p53 activity. (5) Since p53 induces the transcription of miR-34, without p53, the amount of MiR-34 in patients with lithium treatment decreases.
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