Marius Stephan, Sergi Papiol, Mingyue Zhang, Jie Song, Samuel M Frommeyer, Helen Haupt, Niels Jensen, Nirmal Kannaiyan, Rajinder Gupta, Philipp Schuler, Pia Pickelmann, Ruofan Li, Michael McCarthy, Eva C Schulte, Mikael Landen, Peter Falkai, Volker Scheuss, Thomas Schulze, Weiqi Zhang, Moritz J Rossner
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.