Anouar Khayachi, PhD; Ariel Ase, PhD; Calwing Liao, MSc; Anusha Kamesh, MSc; Naila Kuhlmann, PhD; Lenka Schorova, PhD; Boris Chaumette, MD, PhD; Patrick Dion, PhD; Martin Alda, MD, PhD; Philippe Séguéla, PhD; Guy Rouleau, MD, PhD; Austen Milnerwood, PhD
Background: Bipolar disorder is characterized by cyclical alternation between mania and depression, often comorbid with psychosis and suicide. Compared with other medications, the mood stabilizer lithium is the most effective treatment for the prevention of manic and depressive episodes. However, the pathophysiology of bipolar disorder and lithium’s mode of action are yet to be fully understood. Evidence suggests a change in the balance of excitatory and inhibitory activity, favouring excitation in bipolar disorder. In the present study, we sought to establish a holistic understanding of the neuronal consequences of lithium exposure in mouse cortical neurons, and to identify underlying mechanisms of action.
Methods: We used a range of technical approaches to determine the effects of acute and chronic lithium treatment on mature mouse cortical neurons. We combined RNA screening and biochemical and electrophysiological approaches with confocal immunofluorescence and live-cell calcium imaging.
Results: We found that only chronic lithium treatment significantly reduced intracellular calcium flux, specifically by activating metabotropic glutamatergic receptor 5. This was associated with altered phosphorylation of protein kinase C and glycogen synthase kinase 3, reduced neuronal excitability and several alterations to synapse function. Consequently, lithium treatment shifts the excitatory–inhibitory balance toward inhibition.
Limitations: The mechanisms we identified should be validated in future by similar experiments in whole animals and human neurons.
Conclusion: Together, the results revealed how lithium dampens neuronal excitability and the activity of the glutamatergic network, both of which are predicted to be overactive in the manic phase of bipolar disorder. Our working model of lithium action enables the development of targeted strategies to restore the balance of overactive networks, mimicking the therapeutic benefits of lithium but with reduced toxicity.
Submitted Sep. 28, 2020; Revised Dec. 21, 2020; Revised Jan. 20, 2021; Accepted Jan. 30, 2021
Acknowledgements: We gratefully acknowledge the financial supports from Fonds de recherche en santé du Québec, Ellen Foundation and Killam to A.J.M, the Canadian Institutes of Health Research (CIHR) grant (#332971 to G.A.R.), ERA PerMed grant to M.A. and G.A.R., the Healthy Brains for Healthy Lives and Bettencourt–Schueller fondation grants to B.C. and the RI-MUHC 2020 fellowship to L.S. We also thank the microscopy platform of the Montreal Neurological Institute (MNI) and the Molecular Tools Platform of the CERVO Brain Research Centre for providing us the AAV constructs. We would also like to thank the animal care facility of MNI and Bruno Vieira for assistance with mice handling. We also thank Dr. Simon Wing laboratory for the kind gift of reagents. G.A.R. holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences. C.L. is a recipient of the Vanier Canada Graduate Scholarship from the CIHR.
Affiliations: From the Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Que., Canada (Khayachi, Ase, Liao, Kamesh, Kuhlmann, Dion, Séguéla Rouleau, Milnerwood); the Department of Human Genetics, McGill University, Montréal, Que., Canada (Rouleau); McGill University Health Centre Research Institute, Montréal, Que., Canada (Schorova); the Université de Paris, Institut de Psychiatrie et Neuroscience of Paris (IPNP), INSERM U1266, GHU Paris Psychiatrie et Neurosciences, Paris, France (Chaumette); the Department of Psychiatry, McGill University, Montréal Que., Canada (Chaumette); and the Department of Psychiatry, Dalhousie University, Halifax, NS, Canada (Alda).
Competing interests: None declared.
Contributors: A. Khayachi and A. Milnerwood designed the study. A. Khayachi, A. Ase, A. Kamesh, N. Kuhlmann and L. Schorova acquired the data, which A. Khayachi, A. Ase, C. Liao, B. Chaumette, P. Dion, M. Alda, P. Séguéla and G. Rouleau analyzed. A. Khayachi and A. Milnerwood wrote the article, which A. Ase, C. Liao, A. Kamesh, N. Kuhlmann, L. Schorova, B. Chaumette, P. Dion, M. Alda, P. Séguéla and G. Rouleau reviewed. All authors approved the final version to be published and can certify that no other individuals not listed as authors have made substantial contributions to the paper.
Content licence: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BYNC-ND 4.0) licence, which permits use, distribution and reproduction in any medium, provided that the original publication is properly cited, the use is non-commercial (i.e. research or educational use), and no modifications or adaptations are made. See: https://creativecommons.org/licenses/by-nc-nd/4.0/
Correspondence to: A.J. Milnerwood, Department of Neurology and Neurosurgery, McGill University, Montréal, QC H3A 2B4; firstname.lastname@example.org