Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome

Daniela Valenti, Lidia de Bari, Daniele Vigli, Enza Lacivita, Marcello Leopoldo, Giovanni Laviola, Rosa Anna Vacca, Bianca De Filippis

Research output: Contribution to journalArticlepeer-review

Abstract

Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. Recently we have demonstrated that neurobehavioral and brain molecular alterations can be rescued in a RTT mouse model, by pharmacological stimulation of the brain serotonin receptor 7 (5-HT7R). This member of the serotonin receptor family, crucially involved in the regulation of brain structural plasticity and cognitive processes, can be stimulated by systemic repeated treatment with LP-211, a brain-penetrant selective agonist. The present study extends previous findings by demonstrating that LP-211 treatment (0.25 mg/kg, once per day for 7 days) rescues mitochondrial respiratory chain impairment, oxidative phosphorylation deficiency and the reduced energy status in the brain of heterozygous female mice from two highly validated mouse models of RTT (MeCP2-308 and MeCP2-Bird mice). Moreover, LP-211 treatment completely restored the radical species overproduction by brain mitochondria in the MeCP2-308 model and partially recovered the oxidative imbalance in the more severely affected MeCP2-Bird model. These results provide the first evidence that RTT brain mitochondrial dysfunction can be rescued targeting the brain 5-HT7R and add compelling preclinical evidence of the potential therapeutic value of LP-211 as a pharmacological approach for this devastating neurodevelopmental disorder.

Original languageEnglish
Pages (from-to)79-88
Number of pages10
JournalNeuropharmacology
Volume121
DOIs
Publication statusPublished - Jul 15 2017

Keywords

  • Energy metabolism
  • Intellectual disability
  • Neurodevelopmental disorders
  • Oxidative stress
  • Rho GTPases
  • Transgenic mice
  • Rett Syndrome
  • Animal models

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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