Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorder.

Akt and AMPK pathways Bipolar disorder Lithium responsiveness Phosphoproteomics iPSC-derived neurons

Journal

EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039

Informations de publication

Date de publication:
20 May 2024
Historique:
received: 10 10 2023
revised: 30 04 2024
accepted: 06 05 2024
medline: 22 5 2024
pubmed: 22 5 2024
entrez: 21 5 2024
Statut: aheadofprint

Résumé

Bipolar disorder (BD) is a multifactorial psychiatric illness affecting ∼1% of the global adult population. Lithium (Li), is the most effective mood stabilizer for BD but works only for a subset of patients and its mechanism of action remains largely elusive. In the present study, we used iPSC-derived neurons from patients with BD who are responsive (LR) or not (LNR) to lithium. Combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics were employed to provide mechanistic insights into neuronal hyperactivity in BD, investigate Li's mode of action, and identify alternative treatment strategies. We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na These results suggest potential for new treatment strategies in BD, such as Akt activators in LR cases, and the use of AMPK activators for LNR patients with BD. Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation.

Sections du résumé

BACKGROUND BACKGROUND
Bipolar disorder (BD) is a multifactorial psychiatric illness affecting ∼1% of the global adult population. Lithium (Li), is the most effective mood stabilizer for BD but works only for a subset of patients and its mechanism of action remains largely elusive.
METHODS METHODS
In the present study, we used iPSC-derived neurons from patients with BD who are responsive (LR) or not (LNR) to lithium. Combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics were employed to provide mechanistic insights into neuronal hyperactivity in BD, investigate Li's mode of action, and identify alternative treatment strategies.
FINDINGS RESULTS
We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na
INTERPRETATION CONCLUSIONS
These results suggest potential for new treatment strategies in BD, such as Akt activators in LR cases, and the use of AMPK activators for LNR patients with BD.
FUNDING BACKGROUND
Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation.

Identifiants

DOI: 10.1016/j.ebiom.2024.105161 PMID: 38772282
pubmed: 38772282
pii: S2352-3964(24)00196-8
doi: 10.1016/j.ebiom.2024.105161
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

105161

Informations de copyright

Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests All the authors declare no conflict of interest.

Auteurs

Anouar Khayachi (A)

Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada. Electronic address: Anouar.khayachi@mcgill.ca.

Malak Abuzgaya (M)

Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.

Yumin Liu (Y)

Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.

Chuan Jiao (C)

Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, France.

Kurt Dejgaard (K)

McIntyre Institute, Department of Biochemistry, McGill University, Montréal, Quebec, Canada.

Lenka Schorova (L)

McGill University Health Center Research Institute, Montréal, Quebec, Canada.

Anusha Kamesh (A)

Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.

Qin He (Q)

Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, France.

Yuting Cousineau (Y)

Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.

Alessia Pietrantonio (A)

Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.

Nargess Farhangdoost (N)

Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.

Charles-Etienne Castonguay (CE)

Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada.

Boris Chaumette (B)

Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, France; GHU-Paris Psychiatrie et Neurosciences, Hôpital Sainte Anne, Paris, France; Department of Psychiatry, McGill University, Montréal, Quebec, Canada.

Martin Alda (M)

Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada.

Guy A Rouleau (GA)

Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada. Electronic address: Guy.rouleau@mcgill.ca.

Austen J Milnerwood (AJ)

Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada. Electronic address: Austen.milnerwood@mcgill.ca.

Classifications MeSH