Exploration of the therapeutic potential of the HRH3 histamine receptor in MECP2-related disorders.

Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) are disorders caused by decreases and increases in the expression of the transcriptional regulator, Methyl CpG Binding Protein 2 (MeCP2), respectively. 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 mRNA expression of the histamine H3 receptor (HRH3). In the current manuscript, we expanded receptor profiling to additional RTT patient brain samples representing distinct MECP2 mutations and confirmed significantly reduced levels of HRH3 receptor expression in the majority of patients compared to controls. Using mouse models of RTT and MDS, we observed antiparallel changes in Hrh3 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 little to no efficacy in RAMH or pitolisant in modulating behavioral responses in either mouse line.