Evidence map›Paper›PMID 34077150›Full record

ArticleJournal of psychiatry & neuroscience : JPN2021

Chronic lithium treatment alters the excitatory/ inhibitory balance of synaptic networks and reduces mGluR5-PKC signalling in mouse cortical neurons.

Anouar Khayachi, Ariel Ase, Calwing Liao, Anusha Kamesh, Naila Kuhlmann, Lenka Schorova, Boris Chaumette, Patrick Dion, Martin Alda, Philippe Séguéla and 2 more

Open access · diamondAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of psychiatry & neuroscience : JPN, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.

0numbers the graph read from it
0cells of the map it votes in
18citing papers in PubMed
2.6field-weighted citation impact, top 10% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

18 citing papers in PubMed, 32 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 6 institutions in 2 countries.

Anouar KhayachiFrom 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).
Ariel AseFrom 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).
Calwing LiaoFrom 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).
Anusha KameshFrom 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).
Naila KuhlmannFrom 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).
Lenka SchorovaFrom 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).
Boris ChaumetteFrom 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).
Patrick DionFrom 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).
Martin AldaFrom 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).
Philippe SéguélaFrom 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).
Guy RouleauFrom 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).
Austen MilnerwoodFrom 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).
Université Paris Cité · FRInstitut de Psychiatrie et Neurosciences de Paris · FRMcGill University Health Centre · CADalhousie University · CAInserm · FRMontreal Neurological Institute and Hospital · CA

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

AnimalsBipolar DisorderCalciumCells, CulturedCerebral CortexLithium CompoundsMiceNeural InhibitionNeuronsProtein Kinase CReceptor, Metabotropic Glutamate 5Signal TransductionSynapsesCalciumGrm5 protein, mouseLithium CompoundsProtein Kinase CReceptor, Metabotropic Glutamate 5

Identifiers

PMID34077150
PMCPMC8327978
OpenAlexW3165424273

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.