Abstract

Although REM sleep (REMS) is ubiquitous in mammals, the molecular/neural mechanism of REMS regulation remains unknown. We previously established the Dreamless mutant mice exhibiting ~50% reduction in total REMS time (Funato et al., Nature 2016). We identified an SNP specific to Dreamless mice within the Nalcn gene, which leads to a single amino acid change (N315K) of NALCN, a non-selective leak cation channel. To elucidate the responsible brain regions / neuronal subtypes through which NALCN regulates REMS, we generated flox and FLEx (flip-excision) knock-in mice bearing Cre- dependent loss-of-function and gain-of-function Nalcn alleles, respectively. In Nalcn-FLEx mice, we confirmed that the mice crossed with a systemic Cre-expressing line Actb-iCre phenocopied the Dreamless mice on electroencephalogram and electromyogram (EEG/EMG) analyses. In Nalcn-flox mice, we confirmed a neuronal subtype-specific deletion of Nalcn mRNA in adult brain tissues. Recently we observed that NALCN has distinct roles in forebrain and pons-medulla regions for REM sleep regulation, by using Foxg1-IRES-Cre or En1-Cre lines. Now we are analyzing the sleep phenotype of Nalcn genetically-modified mice with detailed sleep stage scoring.