Modulation of neuronal excitability and plasticity by BHLHE41 conveys lithium non-responsiveness
Abstract
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.
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Authors: Marius Stephan, Sergi Papiol, Mingyue Zhang, Jie Song, Samuel Matthew Frommeyer, Helen M. Haupt, Niels Rosendal Jensen, Nirmal Kannaiyan, Rajinder M. Gupta, Philipp Schuler, Pia Picklmann, Ruofan Li, Michael J. McCarthy, Eva C. Schulte, Mikael Landén, Peter Falkai, Volker Scheuß, Thomas G. Schulze, Weiqi Zhang, Moritz J. Rossner
Institutions: Karolinska Institutet, University of California San Diego, Johns Hopkins University, Ludwig-Maximilians-Universität München, Heidelberg University, University Hospital Heidelberg, Instituto de Salud Carlos III, University of Bonn, West China Medical Center of Sichuan University, Centro de Investigación Biomédica en Red de Salud Mental, University of Gothenburg, National Institutes of Health, LMU Klinikum, Max Planck Institute of Psychiatry, University Hospital Bonn, Central Institute of Mental Health, MSH Medical School Hamburg – University of Applied Sciences and Medical University, National Institute of Mental Health, Institut für Psychiatrische Phänomik und Genomik, VA San Diego Healthcare System, Circadian (United States)