Stimulation of the Serotonin Receptor 7 Restores Brain Histone H3 Acetylation and MeCP2 Corepressor Protein Levels in a Female Mouse Model of Rett Syndrome. Issue 3 (18th February 2021)

• Record Type: Journal Article
• 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
• Is Part Of: Journal of neuropathology and experimental neurology. Volume 80:Issue 3(2021)
• Page Start: 265
• Page End: 273
• Publication Date: 2021-02-18
• Subjects: Brain plasticity -- Corepressor complexes -- Histone acetylation -- MeCP2 -- Rett syndrome -- Serotonin receptor 7; Neurology -- Diseases -- Periodicals; Neurology -- Diseases -- Physiopathology -- Periodicals; 616.8047
• DOI: 10.1093/jnen/nlaa158
• Languages: English
• ISSNs: 0022-3069

Abstract

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.