Reciprocal regulation of the H₃ histamine receptor in Rett syndrome and MECP2 Duplication syndrome: implications for...

Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) are disorders caused by reciprocal decreases and increases in the expression of the transcriptional regulator, Methyl CpG Binding Protein 2 (MeCP2). We previously performed an mRNA expression profiling study of the temporal cortex region from patients diagnosed with RTT and corresponding age, postmortem interval, and sex-matched controls. These studies identified a significant reduction in the expression of the histamine H₃ receptor (HRH3). In the current manuscript, we expanded this H₃ receptor profiling to additional RTT patient brain samples representing distinct MECP2 mutations and confirmed significantly reduced levels of H₃ receptor expression in the majority of patients compared to controls. Using mouse models of RTT and MDS, we observed antiparallel changes in H₃ receptor expression across various brain areas, with Hrh3 expression being reduced in RTT model animals and increased in a mouse model of MDS. We then evaluated both a small molecule agonist of the H₃ receptor, (R)-α-methylhistamine (RAMH), and the H₃ receptor inverse agonist, pitolisant (Wakix^®), in RTT and MDS models, respectively, to determine impacts on phenotypes in these disease models. Our results show that RAMH significantly impacted an anxiety phenotype in mice modeling RTT (Mecp ^Null/+ ), but pitolisant had no effect on the behaviors examined here in MDS animals (MECP2 ^Tg1 ).