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 language | English |
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Pages (from-to) | 104-114 |
Number of pages | 11 |
Journal | Neuropharmacology |
Volume | 144 |
DOIs | |
Publication status | Published - 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