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

Animals Bipolar Disorder / drug therapy Calcium / metabolism Cells, Cultured Cerebral Cortex / cytology Lithium Compounds / administration & dosage Mice Neural Inhibition / drug effects Neurons / drug effects Protein Kinase C / antagonists & inhibitors Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors Signal Transduction / drug effects Synapses / drug effects

Journal

Journal of psychiatry & neuroscience : JPN
ISSN: 1488-2434
Titre abrégé: J Psychiatry Neurosci
Pays: Canada
ID NLM: 9107859

Informations de publication

Date de publication:
02 06 2021
Historique:
entrez: 2 6 2021
pubmed: 3 6 2021
medline: 27 1 2022
Statut: epublish

Résumé

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. 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. 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. The mechanisms we identified should be validated in future by similar experiments in whole animals and human neurons. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1503/jpn.200185 PMID: 34077150 PMC: PMC8327978
pubmed: 34077150
doi: 10.1503/jpn.200185
pmc: PMC8327978
doi:

Substances chimiques

Grm5 protein, mouse 0
Lithium Compounds 0
Receptor, Metabotropic Glutamate 5 0
Protein Kinase C EC 2.7.11.13
Calcium SY7Q814VUP

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

E402-E414

Informations de copyright

© 2021 CMA Joule Inc. or its licensors

Déclaration de conflit d'intérêts

None declared.

Références

J Neurosci. 1998 Jul 15;18(14):5294-300
pubmed: 9651212
Nat Rev Neurosci. 2005 Apr;6(4):277-84
pubmed: 15803159
Eur J Neurosci. 2003 Jun;17(12):2573-85
pubmed: 12823464
Front Cell Neurosci. 2014 Sep 05;8:257
pubmed: 25249934
Int J Alzheimers Dis. 2011;2011:189728
pubmed: 21660241
Am J Psychiatry. 2009 Jun;166(6):718-25
pubmed: 19448189
Mol Psychiatry. 2020 Nov;25(11):2800-2817
pubmed: 30504823
J Neurosci Methods. 2013 Apr 30;215(1):60-70
pubmed: 23454685
Transl Psychiatry. 2020 Apr 6;10(1):103
pubmed: 32251271
Neuropharmacology. 2020 Dec 15;181:108357
pubmed: 33065166
Mol Psychiatry. 2018 Feb;23(2):467-475
pubmed: 27752079
Mol Neurobiol. 2011 Dec;44(3):407-19
pubmed: 21983961
Neuropharmacology. 2008 Sep;55(4):474-82
pubmed: 18625255
Int J Bipolar Disord. 2016 Dec;4(1):27
pubmed: 27900734
Psychopharmacology (Berl). 2003 Jul;168(3):344-6
pubmed: 12684737
Neuroscience. 2009 Jul 21;161(4):1126-34
pubmed: 19362133
Mol Psychiatry. 2015 Jun;20(6):661-70
pubmed: 25687772
Nature. 2015 Nov 5;527(7576):95-9
pubmed: 26524527
Eur J Neurosci. 2010 Jun;31(12):2178-84
pubmed: 20550565
ACS Chem Neurosci. 2014 Jun 18;5(6):413-21
pubmed: 24625017
J Biochem. 2002 Nov;132(5):683-7
pubmed: 12417016
Mol Psychiatry. 2003 Feb;8(2):135-44
pubmed: 12610644
Mol Psychiatry. 2005 Jan;10(1):117-26
pubmed: 15558078
Mol Neuropsychiatry. 2017 Nov;3(2):108-124
pubmed: 29230399
Int J Neuropsychopharmacol. 2011 Jun;14(5):618-30
pubmed: 20497624
Neuropsychobiology. 2007;55(3-4):123-31
pubmed: 17641532
J Clin Psychiatry. 2017 Nov/Dec;78(9):e1259-e1269
pubmed: 29188905
Neuroscience. 2008 Feb 19;151(4):1184-97
pubmed: 18222042
Cell Signal. 2011 May;23(5):753-62
pubmed: 20946954
BMJ. 2013 Jun 27;346:f3646
pubmed: 23814104
World Psychiatry. 2016 Feb;15(1):53-8
pubmed: 26833609
Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8363-8
pubmed: 9653192
Nature. 1993 Jan 7;361(6407):31-9
pubmed: 8421494
Neurosci Biobehav Rev. 2009 Mar;33(3):336-54
pubmed: 18955079
J Neurosci. 2004 Jul 21;24(29):6578-89
pubmed: 15269270
Lancet Psychiatry. 2014 Oct;1(5):351-9
pubmed: 26360999
Adv Enzyme Regul. 1996;36:229-44
pubmed: 8869749
Front Pharmacol. 2016 Aug 31;7:295
pubmed: 27630571
Bipolar Disord. 1999 Dec;1(2):81-6
pubmed: 11252663
Mol Psychiatry. 2017 Oct;22(10):1473-1482
pubmed: 28138157
Nat Neurosci. 2011 Mar;14(3):285-93
pubmed: 21346746
Neural Plast. 2019 May 2;2019:4209475
pubmed: 31191636
Ann N Y Acad Sci. 2003 Nov;1003:402-4
pubmed: 14684472
Bipolar Disord. 2001 Apr;3(2):63-7
pubmed: 11333064
Biol Psychiatry. 2008 Oct 15;64(8):718-26
pubmed: 18602089
Proc Natl Acad Sci U S A. 2011 Jan 4;108(1):379-84
pubmed: 21173228
Int J Neuropsychopharmacol. 2014 Oct 31;18(2):
pubmed: 25577667
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2642-7
pubmed: 9482940
J Biol Chem. 2010 Aug 20;285(34):26369-76
pubmed: 20584904
CNS Drugs. 2013 Feb;27(2):135-53
pubmed: 23371914
J Neurosci. 2003 Jul 23;23(16):6586-95
pubmed: 12878700
Learn Mem. 2007 Apr 02;14(4):236-46
pubmed: 17404386
Eur J Pharmacol. 1989 Jul 4;166(1):95-9
pubmed: 2553432
J Affect Disord. 1998 Sep;50(2-3):143-51
pubmed: 9858074
Neuroscience. 2016 May 3;321:163-188
pubmed: 26314632
Exp Mol Med. 2018 Apr 9;50(4):1-11
pubmed: 29628501
Neuronal Signal. 2017 Apr 10;1(2):NS20160005
pubmed: 32714576
Transl Psychiatry. 2021 Jan 11;11(1):36
pubmed: 33431852
Nat Rev Dis Primers. 2018 Mar 08;4:18008
pubmed: 29516993
Nat Commun. 2018 Feb 22;9(1):757
pubmed: 29472612
Bipolar Disord. 2016 May;18(3):261-71
pubmed: 27004755
Nat Genet. 2019 May;51(5):793-803
pubmed: 31043756
Mol Psychiatry. 2003 Aug;8(8):721-37, 715
pubmed: 12888801
Mol Psychiatry. 2001 Sep;6(5):570-8
pubmed: 11526471
Arch Gen Psychiatry. 2000 Apr;57(4):349-56
pubmed: 10768696
Neuropharmacology. 2009 Jan;56(1):47-55
pubmed: 18789340
J Neurosci. 2008 Jan 2;28(1):68-79
pubmed: 18171924
Pharmacol Ther. 2006 Dec;112(3):810-32
pubmed: 16904750
JAMA Psychiatry. 2014 Dec 1;71(12):1323-31
pubmed: 25271938
Proc Natl Acad Sci U S A. 2017 May 30;114(22):E4462-E4471
pubmed: 28500272
Transl Psychiatry. 2015 Nov 10;5:e678
pubmed: 26556287
J Neurosci. 1995 Jan;15(1 Pt 1):1-11
pubmed: 7823120

Auteurs

Anouar Khayachi (A)

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).

Ariel Ase (A)

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).

Calwing Liao (C)

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).

Anusha Kamesh (A)

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).

Naila Kuhlmann (N)

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).

Lenka Schorova (L)

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).

Boris Chaumette (B)

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).

Patrick Dion (P)

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).

Martin Alda (M)

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).

Philippe Séguéla (P)

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).

Guy Rouleau (G)

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).

Austen Milnerwood (A)

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).

Articles similaires

Evaluating the efficacy of telesurgery with dual console SSI Mantra Surgical Robotic System: experiment on animal model and clinical trials.

Sudhir Prem Srivastava, Vishwajyoti Pascual Srivastava, Avinesh Singh et al.
1.00
Robotic Surgical Procedures Animals Humans Telemedicine Models, Animal

Odour generalisation and detection dog training.

Lyn Caldicott, Thomas W Pike, Helen E Zulch et al.
1.00
Animals Odorants Dogs Generalization, Psychological Smell

FBXO22 inhibits colitis and colorectal carcinogenesis by regulating the degradation of the S2448-phosphorylated form of mTOR.

Minle Li, Xuan Chen, Pengfei Qu et al.
1.00
Animals TOR Serine-Threonine Kinases Colorectal Neoplasms Colitis Mice

Use of organic material provided by an automatic enrichment device by weaner pigs and its influence on tail lesions.

Philipp Heseker, Jeanette Probst, Stefanie Ammer et al.
1.00
Animals Tail Swine Behavior, Animal Animal Husbandry

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chronic lithium treatment alters the...
questionsmedicales.fr › Troubles mentaux › Troubles de l'humeur › Troubles bipolaires et apparentés › Trouble bipolaire › Chronic lithium treatment alters the...
questionsmedicales.fr › Facteurs biologiques › Facteurs de la coagulation sanguine › Calcium › Chronic lithium treatment alters the...
questionsmedicales.fr › Cellules › Cellules cultivées › Chronic lithium treatment alters the...
questionsmedicales.fr › Système nerveux › Système nerveux central › Encéphale › Prosencéphale › Télencéphale › Cerveau › Cortex cérébral › Chronic lithium treatment alters the...
questionsmedicales.fr › Produits chimiques inorganiques › Composés du lithium › Chronic lithium treatment alters the...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Chronic lithium treatment alters the...
questionsmedicales.fr › Phénomènes physiologiques de l'appareil locomoteur et du système nerveux › Phénomènes physiologiques du système nerveux › Inhibition nerveuse › Chronic lithium treatment alters the...
questionsmedicales.fr › Cellules › Neurones › Chronic lithium treatment alters the...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Protéine kinase C › Chronic lithium treatment alters the...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs aux neuromédiateurs › Récepteurs aux acides aminés › Récepteurs au glutamate › Récepteurs métabotropes au glutamate › Récepteur-5 métabotropique du glutamate › Chronic lithium treatment alters the...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Chronic lithium treatment alters the...
questionsmedicales.fr › Cellules › Structures cellulaires › Membrane cellulaire › Structures de la membrane cellulaire › Jonctions intercellulaires › Synapses › Chronic lithium treatment alters the...