Akt and AMPK activators rescue hyperexcitability in neurons from patients with bipolar disorderResearch in context
Anouar Khayachi,
Malak Abuzgaya,
Yumin Liu,
Chuan Jiao,
Kurt Dejgaard,
Lenka Schorova,
Anusha Kamesh,
Qin He,
Yuting Cousineau,
Alessia Pietrantonio,
Nargess Farhangdoost,
Charles-Etienne Castonguay,
Boris Chaumette,
Martin Alda,
Guy A. Rouleau,
Austen J. Milnerwood
Affiliations
Anouar Khayachi
Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada; Corresponding author.
Malak Abuzgaya
Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada
Yumin Liu
Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada
Chuan Jiao
Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, France
Kurt Dejgaard
McIntyre Institute, Department of Biochemistry, McGill University, Montréal, Quebec, Canada
Lenka Schorova
McGill University Health Center Research Institute, Montréal, Quebec, Canada
Anusha Kamesh
Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada
Qin He
Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Paris, France
Yuting Cousineau
Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada
Alessia Pietrantonio
Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada
Nargess Farhangdoost
Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada
Charles-Etienne Castonguay
Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada
Boris Chaumette
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
Department of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada
Guy A. Rouleau
Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada; Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Corresponding author.
Austen J. Milnerwood
Montreal Neurological Institute, Department of Neurology & Neurosurgery, McGill University, Montréal, Quebec, Canada; Corresponding author.
Summary: 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: 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: We show a selective rescue of the neuronal hyperactivity phenotype by Li in LR neurons, correlated with changes to Na+ conductance. Whole transcriptome sequencing in BD neurons revealed altered gene expression pathways related to glutamate transmission, alterations in cell signalling and ion transport/channel activity. We found altered Akt signalling as a potential therapeutic effect of Li in LR neurons from patients with BD, and that Akt activation mimics Li effect in LR neurons. Furthermore, the increased neural network activity observed in both LR & LNR neurons from patients with BD were reversed by AMP-activated protein kinase (AMPK) activation. Interpretation: 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: Supported by funding from ERA PerMed, Bell Brain Canada Mental Research Program and Brain & Behavior Research Foundation.
