Deficient LEF1 expression is associated with lithium resistance and hyperexcitability in neurons derived from bipolar disorder patients

Abstract

Bipolar disorder (BD) is a psychiatric condition characterized by depressive and manic episodes that affect 2% of the world population. The first-line long-term treatment for mood stabilization is lithium (Li). Induced pluripotent stem cell modeling of BD using hippocampal dentate gyrus-like neurons derived from Li-responsive (LR) and Li-non-responsive (NR) patients previously showed neuronal hyperexcitability. Li treatment reversed hyperexcitability only on the LR neurons. In this study we searched for specific targets of Li resistance in NR neurons and found that the activity of Wnt/β-catenin signaling pathway was severely affected, with a significant decrease in expression of LEF1. Li targets the Wnt/βcatenin signaling pathway by inhibiting GSK-3β and releasing β-catenin that forms a nuclear complex with TCF/LEF1, activating the Wnt/β-catenin transcription program. Therefore, we propose that downregulation of LEF1 may account for Li resistance in NR neurons. Our results show that valproic acid (VPA), a drug used to treat NR patients that also acts downstream of GSK-3β, upregulated LEF1 and Wnt/β-catenin gene targets, increased transcriptional activity of complex β-catenin/TCF/LEF1 and reduced excitability in NR neurons. Additionally, decreasing LEF1 expression in control neurons using shLEF1 caused hyperexcitability, confirming that the impact of VPA on excitability in NR neurons was connected to changes in LEF1 and in the Wnt/β-catenin pathway. Our results suggest that LEF1 may be a useful target for the discovery of new drugs for BD treatment.

SOX Transcription Factors as Important Regulators of Neuronal and Glial Differentiation During Nervous System Development and Adult Neurogenesis

“…It has been shown that complex network between Wnt/βcatenin pathway, SOX2 and proneural genes regulates the progression from progenitors to neurons and glia cells (Agathocleous et al, 2009). Lack of this coordination leads to aberrant neuronal proliferation and differentiation and contributes to the pathology of psychiatric disorders (Agathocleous et al, 2009;Santos et al, 2021). In the search for specific targets of lithium resistance in the patients with bipolar disorder, Santos et al (2021) conducted comparative transcriptome analysis of the hippocampal dentate gyruslike neurons derived from iPSCs of lithium-responsive and lithium-non-responsive patients.…”

“…Lack of this coordination leads to aberrant neuronal proliferation and differentiation and contributes to the pathology of psychiatric disorders (Agathocleous et al, 2009;Santos et al, 2021). In the search for specific targets of lithium resistance in the patients with bipolar disorder, Santos et al (2021) conducted comparative transcriptome analysis of the hippocampal dentate gyruslike neurons derived from iPSCs of lithium-responsive and lithium-non-responsive patients. First, they have demonstrated that neurons generated from both cohorts exhibited neuronal hyperexcitability compared to control neurons that could be reversed by lithium treatment of the lithium-responsive neurons only (Santos et al, 2021).…”

“…In the search for specific targets of lithium resistance in the patients with bipolar disorder, Santos et al (2021) conducted comparative transcriptome analysis of the hippocampal dentate gyruslike neurons derived from iPSCs of lithium-responsive and lithium-non-responsive patients. First, they have demonstrated that neurons generated from both cohorts exhibited neuronal hyperexcitability compared to control neurons that could be reversed by lithium treatment of the lithium-responsive neurons only (Santos et al, 2021). The study showed that neurons from lithium-non-responsive patients acquire distinct phenotypic characteristics, electrophysiological properties and the response to lithium during differentiation due to the severely affected function of canonic Wnt/β-catenin signaling with a significant decrease in expression of LEF1 (Lymphoid enhancer-binding factor 1) (Santos et al, 2021).…”

“…First, they have demonstrated that neurons generated from both cohorts exhibited neuronal hyperexcitability compared to control neurons that could be reversed by lithium treatment of the lithium-responsive neurons only (Santos et al, 2021). The study showed that neurons from lithium-non-responsive patients acquire distinct phenotypic characteristics, electrophysiological properties and the response to lithium during differentiation due to the severely affected function of canonic Wnt/β-catenin signaling with a significant decrease in expression of LEF1 (Lymphoid enhancer-binding factor 1) (Santos et al, 2021). Interestingly, SOX2 was also up-regulated in lithium-non-responsive neurons compared to control neurons (Santos et al, 2021).…”

Spotlight on Three Rs Progress

“…An in vitro model that permits the study of specific characteristics of bipolar disorder has helped to uncover the molecular mechanisms behind the responses to drug treatment. 1 Lithium has been the standard treatment for stabilising the mood of bipolar patients, but it is not effective in a considerable proportion of cases. Previous work with induced pluripotent stem cell modelling, using hippocampal dentate gyrus-like neurons derived from lithium-responsive (LR) and lithium-non-responsive (NR) patients, showed neuronal hyperexcitability that was reversed only in the LR neurons.…”