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

Rett syndrome (RTT) and MECP2 Duplication syndrome (MDS) are disorders caused by reciprocal decreases and increases, respectively, in expression of the methyl reader protein, Methyl CpG Binding Protein 2 (MeCP2). MeCP2 is a transcriptional regulator that induces changes in the expression of thousands of genes. We previously performed an mRNA expression profiling study of the temporal cortex region from a cohort of autopsy samples 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 RTT patients compared to controls. In the current manuscript, we expand this H ₃ receptor profiling to additional RTT patient brain samples representing distinct disease mutations and confirm 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 reciprocal 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 tested the hypothesis that phenotypes in these mouse models would be sensitive to an H ₃ receptor agonist and antagonist, respectively. This point is particularly salient for MDS, as there are no approved treatments available; encouragingly, however, the H ₃ antagonist/inverse agonist pitolisant (Wakix®) has recently been approved for the treatment of narcolepsy, and we sought here to determine if there was potential to repurpose pitolisant for MDS. We evaluated both a small molecule agonist of the H ₃ receptor, ( R )-α-methylhistamine (RAMH), and pitolisant 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 ).