Work

Reciprocal regulation of the H 3 histamine receptor in Rett syndrome and MECP2 Duplication syndrome: implications for therapeutic development

Year: 2025

Type: preprint

Abstract: 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 H 3 receptor ( HRH3 ). In the current manuscript, we expanded this H 3 receptor profiling to additional RTT patient brain samples representing distinct MECP2 mutations and confirmed significantly reduced levels of H 3 receptor expression in the majority of patients compared to controls. Using mouse models of RTT and MDS, we observed antiparallel changes in H 3 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 H 3 receptor, ( R )-α-methylhistamine (RAMH), and the H 3 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 ).

Source: bioRxiv (Cold Spring Harbor Laboratory)

DOI: 10.1101/2025.10.30.685636