Stimulation of the Serotonin Receptor 7 Restores Brain Histone H3 Acetylation and MeCP2 Corepressor Protein Levels in a Female Mouse Model of Rett Syndrome

• Published in: Journal of neuropathology and experimental neurology Vol. 80; no. 3; pp. 265 - 273
• Main Authors: Napoletani, Giorgia, Vigli, Daniele, Cosentino, Livia, Grieco, Maddalena, Talamo, Maria Cristina, Lacivita, Enza, Leopoldo, Marcello, Laviola, Giovanni, Fuso, Andrea, d’Erme, Maria, De Filippis, Bianca
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-03-2021
• Subjects: Acetylation; Animals; Brain - drug effects; Brain - metabolism; Brain research; Disease Models, Animal; Drug therapy; Female; Gene expression; Health aspects; Histones; Histones - genetics; Histones - metabolism; Methyl-CpG-Binding Protein 2 - genetics; Methyl-CpG-Binding Protein 2 - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Piperazines - pharmacology; Piperazines - therapeutic use; Receptors, Serotonin - metabolism; Rett syndrome; Rett Syndrome - drug therapy; Rett Syndrome - genetics; Rett Syndrome - metabolism; Serotonin agonists; Serotonin Receptor Agonists - pharmacology; Serotonin Receptor Agonists - therapeutic use; Testing; Transcription factors; Italy; MeCP2; Serotonin receptor 7; Brain plasticity; Histone acetylation; Corepressor complexes; Rett syndrome
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1093/jnen/nlaa158

Abstract
Rett syndrome (RTT) is a rare neurological disorder caused by mutations in the X-linked MECP2 gene, characterized by severe behavioral and physiological impairments for which no cure is available. The stimulation of serotonin receptor 7 (5-HT7R) with its selective agonist LP-211 (0.25 mg/kg/day for 7 days) was proved to rescue neurobehavioral alterations in a mouse model of RTT. In the present study, we aimed at gaining insight into the mechanisms underpinning the efficacy of 5-HT7R pharmacological stimulation by investigating its epigenetic outcomes in the brain of RTT female mice bearing a truncating MeCP2 mutation. Treatment with LP-211 normalized the reduced histone H3 acetylation and HDAC3/NCoR levels, and increased HDAC1/Sin3a expression in RTT mouse cortex. Repeated 5-HT7R stimulation also appeared to strengthen the association between NCoR and MeCP2 in the same brain region. A different profile was found in RTT hippocampus, where LP-211 rescued H3 hyperacetylation and increased HDAC3 levels. Overall, the present data highlight a new scenario on the relationship between histone acetylation and serotoninergic pathways. 5-HT7R is confirmed as a pivotal therapeutic target for the recovery of neuronal function supporting the translational value of this promising pharmacological approach for RTT.