Lithium response in bipolar disorder correlates with improved cell viability of patient derived cell lines

Pradip Paul,Sydney Moirangthem,Arun Kandasamy,Odity Mukherjee,Ganesan Venkatasubramanian,Bangalore N Gangadhar,Upinder S Bhalla,Thennarasu Kandavel,John P John,Jitender Saini,A Shyamsundar,Shruti Iyer,Palanimuthu T Sivakumar,Jagadisha Thirthalli,Padinjat Raghu,Urvakhsh Meherwan Mehta,Mathew Varghese,Muralidharan Kesavan,Mitradas M Panicker,Deepak Jayarajan,Vivek Benegal,Prabha S Chandra,Sumantra Chattarji,Janardhanan C Narayanaswamy,Janardhan Y C Reddy,Bhupesh Mehta,B Binukumar,Pratima Murthy,Ravi Kumar Nadella,Kumar Keshav ,Meera Purushottam,Salil K Sukumaran,Naren P Rao ,Anirudh Chellappa ,Malla Bhaskara Rao ,Reeteka Sud,Raghavendra B Nayak ,R Kannan ,Sheetal Ambardar,Sanjeev Jain,Biju Viswanath

doi:10.1038/s41598-020-64202-1

Abstract

Lithium is an effective, well-established treatment for bipolar disorder (BD). However, the mechanisms of its action, and reasons for variations in clinical response, are unclear. We used neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs), from BD patients characterized for clinical response to lithium (using the “Alda scale” and “NIMH Retrospective Life chart method”), to interrogate cellular phenotypes related to both disease and clinical lithium response. NPCs from two biologically related BD patients who differed in their clinical response to lithium were compared with healthy controls. RNA-Seq and analysis, mitochondrial membrane potential (MMP), cell viability, and cell proliferation parameters were assessed, with and without in vitro lithium. These parameters were also examined in LCLs from 25 BD patients (16 lithium responders and 9 non-responders), and 12 controls. MMP was lower in both NPCs and LCLs from BD; but it was reversed with in vitro lithium only in LCLs, and this was unrelated to clinical lithium response. The higher cell proliferation observed in BD was unaffected by in vitro lithium. Cell death was greater in BD. However, LCLs from clinical lithium responders could be rescued by addition of in vitro lithium. In vitro lithium also enhanced BCL2 and GSK3B expression in these cells. Our findings indicate cellular phenotypes related to the disease (MMP, cell proliferation) in both NPCs and LCLs; and those related to clinical lithium response (cell viability, BCL2/GSK3B expression) in LCLs.

Highlights

Lithium is an effective, well-established treatment for bipolar disorder (BD)
A hypothesis-based approach based on existing literature (Supplementary Table 1) found cellular phenotypes related to disease [mitochondrial membrane potential (MMP) and cell proliferation] in neural precursor cells (NPCs) and lymphoblastoid cell lines (LCLs); and those related to lithium treatment response in LCLs
In BD, genetic factors may underlie risk of occurrence of disease, as well as response to treatment. To delineate those mechanisms that could have a bearing on response to lithium, we chose two BD patients from the same family who were discordant in their response to lithium (Fig. 1) and characterized the cellular phenotypes related to disease and lithium treatment

Summary

Introduction

Well-established treatment for bipolar disorder (BD). the mechanisms of its action, and reasons for variations in clinical response, are unclear. RNA-Seq and analysis, mitochondrial membrane potential (MMP), cell viability, and cell proliferation parameters were assessed, with and without in vitro lithium. These parameters were examined in LCLs from 25 BD patients (16 lithium responders and 9 non-responders), and 12 controls. Our findings indicate cellular phenotypes related to the disease (MMP, cell proliferation) in both NPCs and LCLs; and those related to clinical lithium response (cell viability, BCL2/GSK3B expression) in LCLs. Bipolar disorder (BD) is a highly heritable psychiatric illness, having a lifetime prevalence of 1–3%1. A limited number of studies have examined IPSC derived neurons from BD patients who have been clinically characterized for lithium response. Another recent study has identified an altered set-point regulation of CRMP2 (a downstream target of GSK-3B) phosphorylation to be a hallmark of IPSC derived neurons from lithium responsive BD patients[19]

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