Biology subjects

Chaumette, B.

Publications and source records attributed to Chaumette, B..

4 recordsLinked to original sources

bioRxiv2025

Lithium partially rescues gene expression and enhancer activity from heterozygous knockout of AKAP11 while inducing novel differential changes

Bipolar disorder (BD) is a complex psychiatric condition usually requiring long-term treatment. Lithium (Li) remains the most effective mood stabilizer for BD, yet it benefits only a subset of patients, and its precise mechanism of action remains elusive. Exome sequencing has identified AKAP11 (A-kinase anchoring protein 11) as a shared risk gene for BD and schizophrenia (SCZ). Given that both the AKAP11-Protein Kinase A (PKA) complex and Li target and inhibit Glycogen Synthase Kinase-3 beta (GSK3{beta}), we hypothesize that Li may partially normalize the transcriptomic and/or epigenomic alterations observed in heterozygous AKAP11-knockout (Het-AKAP11-KO) iPSC-derived neurons. In this study, we employed genome-wide approaches to assess the effects of Li on the transcriptome and epigenome of human iPSC-derived Het-AKAP11-KO neuronal culture. We show that chronic Li treatment in this cellular model upregulates key pathways that were initially downregulated by Het-AKAP11-KO, several of which have also been reported as downregulated in synapses of BD and SCZ post-mortem brain tissues. Moreover, we demonstrated that Li treatment partially rescues certain transcriptomic alterations resulting from Het-AKAP11-KO, bringing them closer to the WT state. We suggest two possible mechanisms underlying these transcriptomic effects: (1) Li modulates histone H3K27ac levels at intergenic and intronic enhancers, influencing enhancer activity and transcription factor binding, and (2) Li enhances GSK3{beta} serine 9 phosphorylation, impacting WNT/{beta}-catenin signaling and downstream transcription. These findings underscore Lis potential as a therapeutic agent for BD and SCZ patients carrying AKAP11 loss-of-function variants or exhibiting similar pathway alterations to those observed in Het-AKAP11-KO models.

genomics↗

bioRxiv2024

Transcriptomic and epigenomic consequences of heterozygous loss of function mutations in AKAP11, the first large-effect shared risk gene for bipolar disorder and schizophrenia

The gene A-kinase anchoring protein 11 (AKAP11) recently emerged as a shared risk factor between bipolar disorder and schizophrenia, driven by large-effect loss-of-function (LoF) variants. Recent research has uncovered the neurophysiological characteristics and synapse proteomics profile of Akap11-mutant mouse models. Considering the role of AKAP11 in binding cAMP-dependent protein kinase A (PKA) and mediating phosphorylation of numerous substrates, such as transcription factors and epigenetic regulators, and given that chromatin alterations have been implicated in the brains of patients with bipolar disorder and schizophrenia, it is crucial to uncover the transcriptomic and chromatin dysregulations following the heterozygous knockout of AKAP11, particularly in human neurons. In this study, we use genome-wide approaches to investigate such aberrations in human induced pluripotent stem cell (iPSC)-derived neurons. We show the impact of heterozygous AKAP11 LoF mutations on the gene expression landscape and profile the methylomic and acetylomic modifications. Altogether we highlight the involvement of aberrant activity of intergenic and intronic enhancers, which are enriched in PBX homeobox 2 (PBX2) and Nuclear Factor-1 (NF1) known binding motifs, respectively, in transcription dysregulations of genes functioning as DNA-binding transcription factors, actin and cytoskeleton regulators, and cytokine receptors, as well as genes involved in G-protein-coupled receptors (GPCRs) binding and signaling. A better understanding of the dysregulations resulting from haploinsufficiency in AKAP11 improves our knowledge of the biological roots and pathophysiology of BD and SCZ, paving the way for better therapeutic approaches.

genomics↗

bioRxiv2023

Molecular signatures of hyperexcitability and lithium responsiveness in bipolar disorder patient neurons provide alternative therapeutic strategies.

Bipolar disorder (BD) is a multifactorial psychiatric illness affecting about 1% of the world population. The first line treatment, lithium (Li), is effective in only a subset of patients and its mechanism of action remains largely elusive. In the present study, we used iPSC-derived neurons from BD patients responsive (LR) or not (LNR) to lithium and combined electrophysiology, calcium imaging, biochemistry, transcriptomics, and phosphoproteomics to report mechanistic insights into neuronal hyperactivity in BD, and Lis mode of action. We show a selective rescue of neuronal hyperactivity by Li in BD LR neurons through changes in Na+ currents. The whole transcriptome sequencing revealed altered gene expression in BD neurons in pathways related to glutamatergic transmission, and Li selectively altered those involved in cell signaling and ion transport/channel activity. We found the therapeutic effect of Li in BD LR patients was associated with Akt signaling and confirmed that an Akt activator mimics Li effect in BD LR neurons. Further, we showed that AMP-activated protein kinase (AMPK) reduces neural network activity and sodium currents in BD LNR patients. These findings suggest the potential for novel treatment strategies in BD, such as Akt activators in BD LR cases, and the use of AMPK activators for BD LNR patients.

neuroscience↗

bioRxiv2020

Chronic lithium treatment alters the excitatory/inhibitory balance of synaptic networks and reduces mGluR5-PKC signaling

Bipolar disorder (BD) is characterized by cyclical alternations between mania and depression, often comorbid with psychosis, and suicide. The mood stabilizer lithium, compared to other medications, is the most efficient treatment for prevention of manic and depressive episodes. The pathophysiology of BD, and lithiums mode of action, are yet to be fully understood. Evidence suggests a change in the balance of excitatory/inhibitory activity, favouring excitation in BD. Here, we sought to establish a holistic appreciation of the neuronal consequences of lithium exposure in mouse cortical neurons and identify underlying mechanisms. We found that chronic (but not acute) lithium treatment significantly reduced intracellular calcium flux, specifically through the activation of the metabotropic glutamatergic receptor mGluR5. This was associated with altered phosphorylation of PKC and GSK3 kinases, reduced neuronal excitability, and several alterations to synapse function. Consequently, lithium treatment shifts the excitatory/inhibitory balance in the network toward inhibition. Together, the results revealed how lithium dampens neuronal excitability and glutamatergic network activity, which are predicted to be overactive in the manic phase of BD. 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.

neuroscience↗