Modulation of neuronal excitability and plasticity by BHLHE41 conveys lithium non-responsiveness
Abstract Many bipolar disorder (BD) patients are non-responsive to lithium. The mechanisms underlying lithium (non-)responsiveness are largely unknown. By using gene-set enrichment analysis methods, we found that core clock gene-sets are significantly associated with lithium response. Among the top hits was BHLHE41 , a modulator of the molecular clock and homeostatic sleep. Since BHLHE41 and its paralog BHLHE40 are functionally redundant, we assessed chronic lithium response in double-knockout mutant mice (DKO). We demonstrated that DKOs are non-responsive to lithium’s effect in various behavioral tasks. Cellular assays and patch clamp recordings revealed lowered excitability and reduced lithium-response in prefrontal cortical layer 2/3 DKO neurons and on hippocampal long-term potentiation. Single-cell RNA sequencing identified that lithium deregulated mitochondrial respiration, cation channel and postsynapse associated gene-sets specifically in upper layer excitatory neurons. Our findings show that lithium acts in a highly cell-specific way on neuronal metabolism and excitability and modulates synaptic plasticity depending on BHLHE40/41.
Authors
- Rajinder M. Gupta
- Volker Scheuß (ORCID: https://orcid.org/0000-0002-0659-3228)
- Marius Stephan (ORCID: https://orcid.org/0000-0003-1889-3049)
- Mikael Landén (ORCID: https://orcid.org/0000-0002-4496-6451)
- Niels Rosendal Jensen (ORCID: https://orcid.org/0000-0002-4526-8401)
- Moritz J. Rossner (ORCID: https://orcid.org/0000-0002-0667-3420)
- Sergi Papiol (ORCID: https://orcid.org/0000-0001-9366-8728)
- Thomas G. Schulze (ORCID: https://orcid.org/0000-0001-6624-2975)
- Helen M. Haupt
- Nirmal Kannaiyan (ORCID: https://orcid.org/0000-0002-7408-6842)
- Peter Falkai (ORCID: https://orcid.org/0000-0002-0284-2290)
- Ruofan Li (ORCID: https://orcid.org/0000-0001-7746-9569)
- Jie Song (ORCID: https://orcid.org/0000-0002-7357-2136)
- Mingyue Zhang (ORCID: https://orcid.org/0000-0002-2293-8847)
- Michael J. McCarthy (ORCID: https://orcid.org/0000-0001-6219-4945)
- Samuel Matthew Frommeyer
- Philipp Schuler
- Pia Picklmann
- Eva C. Schulte
- Weiqi Zhang
Institutions
- National Institutes of Health (US)
- University of Bonn (DE)
- Johns Hopkins University (US)
- Heidelberg University (DE)
- University Hospital Bonn (DE)
- West China Medical Center of Sichuan University (CN)
- Instituto de Salud Carlos III (ES)
- University Hospital Heidelberg (DE)
- Karolinska Institutet (SE)
- LMU Klinikum (DE)
- University of California San Diego (US)
- MSH Medical School Hamburg – University of Applied Sciences and Medical University (DE)
- Centro de Investigación Biomédica en Red de Salud Mental (ES)
- VA San Diego Healthcare System (US)
- Central Institute of Mental Health (DE)
- Circadian (United States) (US)
- Max Planck Institute of Psychiatry (DE)
- National Institute of Mental Health (US)
- Institut für Psychiatrische Phänomik und Genomik (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Gothenburg (SE)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2026-08-18
- DOI
- https://doi.org/10.1038/s41380-026-03822-x
- Citations
- 1
- Primary Topic
- Bipolar Disorder and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Veterans Affairs
- Bundesministerium für Bildung und Forschung