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<p>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 <i>AKAP11</i> (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 (GSK3β), we hypothesize that Li may partially normalize the transcriptomic and/or epigenomic alterations observed in heterozygous <i>AKAP11</i>-knockout (Het-<i>AKAP11</i>-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-<i>AKAP11</i>-KO neuronal culture. We show that chronic Li treatment in this cellular model upregulates key pathways that were initially downregulated by Het-<i>AKAP11</i>-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-<i>AKAP11</i>-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 GSK3β serine 9 phosphorylation, impacting WNT/β-catenin signaling and downstream transcription. These findings underscore Li’s potential as a therapeutic agent for BD and SCZ patients carrying <i>AKAP11</i> loss-of-function variants or exhibiting similar pathway alterations to those observed in Het-<i>AKAP11</i>-KO models.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月29日

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  • Nargess Farhangdoost,
  • Alessia Pietrantonio,
  • Yumin Liu,
  • Calwing Liao,
  • Daniel Rochefort,
  • Alain Pacis,
  • Martin Alda,
  • Patrick A. Dion,
  • Boris Chaumette,
  • Anouar Khayachi,
  • Guy A. Rouleau

摘要

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 (GSK3β), 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 GSK3β serine 9 phosphorylation, impacting WNT/β-catenin signaling and downstream transcription. These findings underscore Li’s 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.