Close

Circadian rhythms in bipolar disorder patient-derived neurons predict lithium response

Himanshu K. Mishra, Noelle M. Ying, Angelica Luis, Heather Wei, Metta Nguyen, Timothy Nakhla, Sara Vandenburgh, Martin Alda, Wade H. Berrettini, Kristen J. Brennand, Joseph R. Calabrese, William H. Coryell, Mark A. Frye, Fred H. Gage, Elliot S. Gershon, Melvin G. McInnis, Caroline M. Nievergelt, John I. Nurnberger, Paul D. Shilling, Ketil J. Oedegaard, Peter P. Zandi, The Pharmacogenomics of Bipolar Disorder Study, John R. Kelsoe, David K Welsh, Michael J. McCarthy

Posted on: 19 January 2021

Preprint posted on 15 December 2020

Broken clocks and mood swings: The link between circadian clock changes and Lithium treatment in Bipolar disorder patients.

Selected by Sejal Davla

Categories: cell biology, neuroscience

Introduction

Sleep and circadian rhythm disruptions are highly prevalent in patients with neuropsychiatric disorders. Bipolar disorder (BD) is one of the major neuropsychiatric illnesses characterized by cognitive dysfunction, mood changes and sleep/activity pattern shifts. Insomnia and poor sleep quality are some of the most widespread symptoms in BD and these sleep disturbances are often good predictors of mood swings. Hence establishing the stability of sleep-wake and circadian cycles is a key therapeutic strategy in BD patients1.

Lithium is a wonder drug that everyone knows about as a mood stabilizer in BD patients. Lithium is shown to be a definitive neuroprotective agent in BD with beneficial effects in the prevention of severe mood changes, psychosis and suicide2. While Lithium continues to be the main pharmacotherapy drug for the treatment of BD, 30-40% of patients fail to respond to the treatment. BD is a complex, polygenic disorder where patients display heterogeneous genotypic and phenotypic disparities. Lithium responsiveness, therefore, can be an alternate strategy to reduce heterogeneity in clinical studies.

Lithium treatment altered phase and period of circadian activity patterns in many animal models and fibroblast cells harvested from BD patients. Besides, chronotype is a predictor of Lithium response where patients with ‘high morningness’ show higher Li responsiveness3. While animal models are informative to chart out behavioral and pathological hallmarks of Li responsiveness, human cellular models are irreplaceable in understanding biological mechanisms of Lithium response in BD patients.

Patient-derived induced pluripotent stem cells (iPSCs) provide an excellent tool to characterize the etiology of any human disease. A recent preprint from Mishra et al investigates the cellular and molecular changes in circadian rhythmicity from patient-derived iPSCs from Lithium-responsive and non-responsive BD patients.

About the preprint

Circadian rhythm is a ubiquitous, cell-autonomous process that displays an oscillation of around 24-hours. Circadian rhythms are generated and regulated by circadian clock genes whose mRNA and protein products oscillate in a periodic manner. The clock genes are expressed in all tissues but are required specifically in central clock neurons that communicate with each other to generate a synchronous circadian output. How does the clock function in the neurons of BD patients had not been investigated before. The authors in this manuscript use live imaging and gene expression analyses to identify the relationship between Lithium response and circadian rhythm disruption in BD patients.

The authors tested a cohort of BD patients and chose the most and least lithium responsive people to harvest skin cells for the study. Bioluminescence reporters are crucial in the studies of circadian molecular oscillators. The authors used luciferase activity of core clock gene PER2 in iPSC-derived neuronal precursor cells (NPCs) and glutamatergic neurons to compare and contrast the hallmarks of circadian rhythmicity in healthy vs lithium-responsive and non-responsive BD patients.

Time series analysis

Using live imaging time series analysis, Mishra et al unraveled profound circadian rhythm disruptions in BD cells, particularly in cells from Lithium non-responders. Control and Lithium-responsive NPCs and neurons displayed robust, high amplitude period rhythms whereas cells from lithium non-responders showed weak, low-amplitude rhythms and faster rhythm dampening. The only identifiable difference between control and Lithium responder cells was observed in NPCs where period length was significantly shorter in BD NPCs compared to controls.

Another crucial difference in rhythmicity was identified in healthy control cell lines where differentiated mature neurons were more rhythmic compared to NPCs. Meanwhile, the overall proportion and rhythmicity of neurons remained similar to NPCs in BD cell lines. The authors further analyzed cells that were highly rhythmic to identify phase differences. Control NPCs and neurons showed clustered phase compared to BD cells with dispersed phase. When the authors treated these cells with Lithium, they further identified a concentration-dependent effect on period lengthening in control and Lithium responder cells. As expected, Lithium treatment had no effect on Lithium non-responder cells.

Gene expression changes

The authors also analyzed the levels of seven core clock genes that provided the contribution of the molecular clock network in the circadian disruption phenotypes observed in the luciferase assay. Among the clock genes, BD cells showed a significant increase in PER2 mRNA and protein levels. The overexpression of PER2 which is a negative regulator of the clock might explain the weak rhythmicity phenotype in BD cells. Among the BD cohort, the Lithium responder neurons had higher CRY1 and BMAL1 mRNA expression compared to the Lithium non-responder neurons. This particular observation might pave the way in developing new targets for drug therapies to correct circadian rhythmicity defects in BD patients.

Circadian Entrainment

The ability to synchronize circadian activity at different temperatures is an important feature of circadian systems. When the authors used a temperature ramp entrainment protocol where cells experienced different temperatures every 12 hours, all groups displayed an increase in the amplitude of the rhythm and a more synchronized and lasting rhythm. This result is valuable for the Lithium non-responsive BD cohort in the management of circadian disruptions in using temperature entrainment protocols.

Why I chose this preprint

Lithium is an old drug with promising beneficial effects not just in BD but also in depression, psychosis and a number of neurodegenerative disorders. The molecular and cellular targets of Lithium’s action are numerous. Work from McCarthy and colleagues directly demonstrates circadian disruptions in patient-derived neurons. I chose to highlight this preprint because it undoubtedly provides an important framework for future large-scale studies in iPSC cell lines to characterize circadian disruptions in BD patients with varying genetic backgrounds. Further, the use of the circadian entrainment technique to improve cellular rhythmicity and stabilize sleep disturbances in Lithium non-responsive BD patients might lead to a game-changing therapeutic strategy.

Questions to the authors

  1. Were the Lithium responder BD patients on Lithium therapy when their skin cells were harvested for iPSC? This clarification will be helpful to interpret the nature of Lithium effect on circadian rhythms (short-term vs long-term).
  2. What percentage of Lithium non-responder neurons showed increased amplitude under temperature ramp conditions?
  3. Did the temperature entrainment alter PER2 levels in Lithium non-responsive neurons?
  4. Are there any genetic forms of BD that show higher Lithium non-responsiveness?

References:

  1. Steardo L Jr, de Filippis R, Carbone EA, Segura-Garcia C, Verkhratsky A, De Fazio P. Sleep Disturbance in Bipolar Disorder: Neuroglia and Circadian Rhythms. Front Psychiatry. 2019;10:501. Published 2019 Jul 18. doi:10.3389/fpsyt.2019.00501
  2. Machado-Vieira R, Manji HK, Zarate CA Jr. The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis. Bipolar Disord. 2009;11 Suppl 2(Suppl 2):92-109. doi:10.1111/j.1399-5618.2009.00714.x
  3. McCarthy, M.J., Wei, H., Nievergelt, C.M. et al. Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder. Neuropsychopharmacol 44, 620–628 (2019). https://doi.org/10.1038/s41386-018-0273-8

 

 

doi: https://doi.org/10.1242/prelights.27072

Read preprint (No Ratings Yet)

Author's response

Michael McCarthy shared

We are really excited that the method we developed to study rhythms in human clinical samples using fibroblasts translated so well into the iPSC-neuron model. It will add nicely to the experimental tools available to researchers to study other neuronal models of psychiatric disorders. The demonstration of rhythm deficits in bipolar disorder neurons shows that the dimension of time is important to consider in future studies.

Questions to the authors

  1.  Were the Lithium responder BD patients on Lithium therapy when their skin cells were harvested for iPSC? This clarification will be helpful to interpret the nature of Lithium effect on circadian rhythms (short-term vs long-term).
    Yes- all of the patients, both responders and non-responders were on lithium when they gave us the biopsy.  However, we don’t think the exposure to lithium at the time of the biopsy plays a major role in our findings. The cells were cultured and passaged several times before the experiments were performed, as well as re-programmed into iPSC, then differentiated into neurons. After all of that, the residual amount of lithium in the cell cultures would be expected to be vanishingly low, and too low for a pharmacological effect of lithium. We can’t rule out that lithium exposure caused some other kind of long-lasting changes to the cells (i.e. epigenetic modifications), but we are confident we washed out any transient drug effects. We expect that the effects we saw relate more to stable genetic differences in the cells that impact circadian rhythms and/or bipolar disorder.
  2. What percentage of Lithium non-responder neurons showed increased amplitude under temperature ramp conditions?  The sample size is too small to say with any certainty. This is an area we hope to study more in the future.
  3. Did the temperature entrainment alter PER2 levels in Lithium non-responsive neurons? Previous work in mice has shown that entrainment to light causes upregulation of another clock gene, PER1. A similar mechanism may be present in the temperature cycle experiments we conducted in neurons, but we did not measure gene expression or protein for any of the clock genes under these conditions.
  4. Are there any genetic forms of BD that show higher Lithium non-responsiveness? Genome-wide association studies have shown genetic differences between lithium responders and non-responders (see Hou et al Lancet 2016, Amare et al JAMA Psych 2017, Amare et al Mol Psych 2020). There are some clinical features that may predict a good response as well including strong family history, euphoric manias, and a symptom course of mania followed by depression.

 

Have your say

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

Also in the cell biology category:

Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder

Thomas Larrieu, Charline Carron, Fabio Grieco, et al.

Selected by 04 December 2024

Harvey Roweth

Neuroscience

Investigating Mechanically Activated Currents from Trigeminal Neurons of Non-Human Primates

Karen A Lindquist, Jennifer Mecklenburg, Anahit H. Hovhannisyan, et al.

Selected by 04 December 2024

Vanessa Ehlers

Neuroscience

Motor Clustering Enhances Kinesin-driven Vesicle Transport

Rui Jiang, Qingzhou Feng, Daguan Nong, et al.

Selected by 16 November 2024

Sharvari Pitke

Biophysics

Also in the neuroscience category:

Platelet-derived LPA16:0 inhibits adult neurogenesis and stress resilience in anxiety disorder

Thomas Larrieu, Charline Carron, Fabio Grieco, et al.

Selected by 04 December 2024

Harvey Roweth

Neuroscience

Investigating Mechanically Activated Currents from Trigeminal Neurons of Non-Human Primates

Karen A Lindquist, Jennifer Mecklenburg, Anahit H. Hovhannisyan, et al.

Selected by 04 December 2024

Vanessa Ehlers

Neuroscience

Circadian modulation of mosquito host-seeking persistence by Pigment-Dispersing Factor impacts daily biting patterns

Linhan Dong, Richard Hormigo, Jord M. Barnett, et al.

Selected by 29 November 2024

Javier Cavieres

Neuroscience

preLists in the cell biology category:

November in preprints – the CellBio edition

This is the first community-driven preList! A group of preLighters, with expertise in different areas of cell biology, have worked together to create this preprint reading lists for researchers with an interest in cell biology. Categories include: 1) cancer cell biology 2) cell cycle and division 3) cell migration and cytoskeleton 4) cell organelles and organisation 5) cell signalling and mechanosensing 6) genetics/gene expression

 



List by Felipe Del Valle Batalla et al.

BSCB-Biochemical Society 2024 Cell Migration meeting

This preList features preprints that were discussed and presented during the BSCB-Biochemical Society 2024 Cell Migration meeting in Birmingham, UK in April 2024. Kindly put together by Sara Morais da Silva, Reviews Editor at Journal of Cell Science.

 



List by Reinier Prosee

‘In preprints’ from Development 2022-2023

A list of the preprints featured in Development's 'In preprints' articles between 2022-2023

 



List by Alex Eve, Katherine Brown

preLights peer support – preprints of interest

This is a preprint repository to organise the preprints and preLights covered through the 'preLights peer support' initiative.

 



List by preLights peer support

The Society for Developmental Biology 82nd Annual Meeting

This preList is made up of the preprints discussed during the Society for Developmental Biology 82nd Annual Meeting that took place in Chicago in July 2023.

 



List by Joyce Yu, Katherine Brown

CSHL 87th Symposium: Stem Cells

Preprints mentioned by speakers at the #CSHLsymp23

 



List by Alex Eve

Journal of Cell Science meeting ‘Imaging Cell Dynamics’

This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.

 



List by Helen Zenner

9th International Symposium on the Biology of Vertebrate Sex Determination

This preList contains preprints discussed during the 9th International Symposium on the Biology of Vertebrate Sex Determination. This conference was held in Kona, Hawaii from April 17th to 21st 2023.

 



List by Martin Estermann

Alumni picks – preLights 5th Birthday

This preList contains preprints that were picked and highlighted by preLights Alumni - an initiative that was set up to mark preLights 5th birthday. More entries will follow throughout February and March 2023.

 



List by Sergio Menchero et al.

CellBio 2022 – An ASCB/EMBO Meeting

This preLists features preprints that were discussed and presented during the CellBio 2022 meeting in Washington, DC in December 2022.

 



List by Nadja Hümpfer et al.

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria

 



List by Dey Lab, Samantha Seah

1

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

 



List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

 



List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

MitoList

This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

 



List by Sandra Franco Iborra

Biophysical Society Annual Meeting 2019

Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA

 



List by Joseph Jose Thottacherry

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.

 



List by Dey Lab, Amanda Haage

Also in the neuroscience category:

2024 Hypothalamus GRC

This 2024 Hypothalamus GRC (Gordon Research Conference) preList offers an overview of cutting-edge research focused on the hypothalamus, a critical brain region involved in regulating homeostasis, behavior, and neuroendocrine functions. The studies included cover a range of topics, including neural circuits, molecular mechanisms, and the role of the hypothalamus in health and disease. This collection highlights some of the latest advances in understanding hypothalamic function, with potential implications for treating disorders such as obesity, stress, and metabolic diseases.

 



List by Nathalie Krauth

‘In preprints’ from Development 2022-2023

A list of the preprints featured in Development's 'In preprints' articles between 2022-2023

 



List by Alex Eve, Katherine Brown

CSHL 87th Symposium: Stem Cells

Preprints mentioned by speakers at the #CSHLsymp23

 



List by Alex Eve

Journal of Cell Science meeting ‘Imaging Cell Dynamics’

This preList highlights the preprints discussed at the JCS meeting 'Imaging Cell Dynamics'. The meeting was held from 14 - 17 May 2023 in Lisbon, Portugal and was organised by Erika Holzbaur, Jennifer Lippincott-Schwartz, Rob Parton and Michael Way.

 



List by Helen Zenner

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

SDB 78th Annual Meeting 2019

A curation of the preprints presented at the SDB meeting in Boston, July 26-30 2019. The preList will be updated throughout the duration of the meeting.

 



List by Alex Eve

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Young Embryologist Network Conference 2019

Preprints presented at the Young Embryologist Network 2019 conference, 13 May, The Francis Crick Institute, London

 



List by Alex Eve
Close