Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder

Daniele Vigli, Laura Rusconi, Daniela Valenti, Paolo La Montanara, Livia Cosentino, Enza Lacivita, Marcello Leopoldo, Elena Amendola, Cornelius Gross, Nicoletta Landsberger, Giovanni Laviola, Charlotte Kilstrup-Nielsen, Rosa A Vacca, Bianca De Filippis

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause CDKL5 Deficiency Disorder (CDD), a rare neurodevelopmental syndrome characterized by severe behavioural and physiological symptoms. No cure is available for CDD. CDKL5 is a kinase that is abundantly expressed in the brain and plays a critical role in neurodevelopmental processes, such as neuronal morphogenesis and plasticity. This study provides the first characterization of the neurobehavioural phenotype of 1 year old Cdkl5-null mice and demonstrates that stimulation of the serotonin receptor 7 (5-HT7R) with the agonist molecule LP-211 (0.25 mg/kg once/day for 7 days) partially rescues the abnormal phenotype and brain molecular alterations in Cdkl5-null male mice. In particular, LP-211 treatment completely normalizes the prepulse inhibition defects observed in Cdkl5-null mice and, at a molecular level, restores the abnormal cortical phosphorylation of rpS6, a downstream target of mTOR and S6 kinase, which plays a direct role in regulating protein synthesis. Moreover, we demonstrate for the first time that mitochondria show prominent functional abnormalities in Cdkl5-null mouse brains that can be restored by pharmacological stimulation of brain 5-HT7R.

Original languageEnglish
Pages (from-to)104-114
Number of pages11
JournalNeuropharmacology
Volume144
DOIs
Publication statusPublished - Jan 2019

Keywords

  • Animals
  • Behavior, Animal/drug effects
  • Brain/drug effects
  • Disease Models, Animal
  • Disease Progression
  • Epileptic Syndromes/drug therapy
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria/drug effects
  • Phosphorylation/drug effects
  • Piperazines/pharmacology
  • Prepulse Inhibition/drug effects
  • Protein-Serine-Threonine Kinases/deficiency
  • Random Allocation
  • Receptors, Serotonin/metabolism
  • Serotonin Receptor Agonists/pharmacology
  • Spasms, Infantile/drug therapy

Fingerprint Dive into the research topics of 'Rescue of prepulse inhibition deficit and brain mitochondrial dysfunction by pharmacological stimulation of the central serotonin receptor 7 in a mouse model of CDKL5 Deficiency Disorder'. Together they form a unique fingerprint.

Cite this