Journal of Molecular Neuroscience

, Volume 62, Issue 3–4, pp 304–308 | Cite as

Evidence towards RNA Binding Motif (RNP1, RRM) Protein 3 (RBM3) as a Potential Biomarker of Lithium Response in Bipolar Disorder Patients

  • Eleni Merkouri Papadima
  • Paola Niola
  • Carla Melis
  • Claudia Pisanu
  • Donatella Congiu
  • Cristiana Cruceanu
  • Juan Pablo Lopez
  • Gustavo Turecki
  • Raffaella Ardau
  • Giovanni Severino
  • Caterina Chillotti
  • Maria Del Zompo
  • Alessio SquassinaEmail author


Lithium has been used for more than six decades for the management of bipolar disorder (BD). In a previous transcriptomic study, we showed that patients affected by either BD or cluster headache, both disorders characterized by circadian disturbances and response to lithium in a subgroup of patients, have higher expression of the RNA binding motif (RNP1, RRM) protein 3 (RBM3) gene compared to controls. To investigate whether RBM3 could represent a biomarker of lithium response, we screened raw microarray expression data from lymphoblastoid cell lines (LCLs) derived from 20 BD patients, responders or non-responders to lithium. RBM3 was the most significantly differentially expressed gene in the list, being overexpressed in responders compared to non-responders (fold change = 2.0; p = 1.5 × 10−16). We therefore sought to validate the microarray finding by quantitative reverse transcription polymerase chain reaction (RT-qPCR) and explore whether RBM3 expression was modulated by lithium treatment in vitro in LCLs as well as in human-derived neural progenitor cells (NPCs). Our findings confirmed the higher expression of RBM3 in responders compared to non-responders (fold change = 3.78; p = 0.0002). Lithium did not change RBM3 expression in LCLs in any of the groups, but it increased its expression in NPCs. While preliminary, our data suggest that higher levels of RBM3 might be required for better lithium response and that the expression of this gene could be modulated by lithium in a tissue-specific manner.


Circadian rhythm Gene expression Lithium response Neuroprotection Bipolar disorder Mood stabilizers 



Bipolar disorder


RNA binding motif (RNP1, RRM) protein 3


Lymphoblastoid cell lines


Quantitative reverse transcription polymerase chain reaction


Neural progenitor cells


Fold change


Excellent responders




Cluster headache


Differentially expressed genes


Induced pluripotent stem cell


Comparative Ct method


False discovery rate


Nitric oxide

Nr1d1, NR1D1

Nuclear receptor subfamily 1 group D member 1


Glycogen synthase kinase 3 beta


Insulin-like growth factor 1


Peripheral blood mononuclear cells



This work was partially funded by a grant from Regione Autonoma della Sardegna (RAS), L7/2007, 2013, call 2013, grant number: 79506. Moreover, the authors wish to thank the patients and their families for participating in this study.

Compliance with Ethical Standards

Our study has been carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki) for experiments involving humans, was approved by the ethics committee of the Teaching Hospital of Cagliari (Italy), and written informed consent was obtained from all participants.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Supplementary material

12031_2017_938_MOESM1_ESM.xlsx (1018 kb)
Online resource 1 Full list of differentially expressed genes with False Discovery Rate (FDR) smaller than 0.05. Microarray data from comparing bipolar disorder patients, responders and non-responders to lithium. (XLSX 1018 kb)


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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Eleni Merkouri Papadima
    • 1
  • Paola Niola
    • 1
  • Carla Melis
    • 1
  • Claudia Pisanu
    • 1
  • Donatella Congiu
    • 1
  • Cristiana Cruceanu
    • 2
  • Juan Pablo Lopez
    • 2
  • Gustavo Turecki
    • 2
  • Raffaella Ardau
    • 3
  • Giovanni Severino
    • 1
  • Caterina Chillotti
    • 3
  • Maria Del Zompo
    • 1
    • 3
  • Alessio Squassina
    • 1
    Email author
  1. 1.Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, School of MedicineUniversity of CagliariCagliariItaly
  2. 2.McGill Group for Suicide Studies, Douglas Mental Health University InstituteMcGill UniversityMontrealCanada
  3. 3.Unit of Clinical Pharmacology of the University Hospital of CagliariCagliariItaly

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