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 |
|---|---|
| Pages (from-to) | 104-114 |
| Number of pages | 11 |
| Journal | Neuropharmacology |
| Volume | 144 |
| DOIs | |
| Publication status | Published - Jan 2019 |
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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
Cite this
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. / Vigli, Daniele; Rusconi, Laura; Valenti, Daniela; La Montanara, Paolo; Cosentino, Livia; Lacivita, Enza; Leopoldo, Marcello; Amendola, Elena; Gross, Cornelius; Landsberger, Nicoletta; Laviola, Giovanni; Kilstrup-Nielsen, Charlotte; Vacca, Rosa A; De Filippis, Bianca.
In: Neuropharmacology, Vol. 144, 01.2019, p. 104-114.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - 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
AU - Vigli, Daniele
AU - Rusconi, Laura
AU - Valenti, Daniela
AU - La Montanara, Paolo
AU - Cosentino, Livia
AU - Lacivita, Enza
AU - Leopoldo, Marcello
AU - Amendola, Elena
AU - Gross, Cornelius
AU - Landsberger, Nicoletta
AU - Laviola, Giovanni
AU - Kilstrup-Nielsen, Charlotte
AU - Vacca, Rosa A
AU - De Filippis, Bianca
N1 - Copyright © 2018 Elsevier Ltd. All rights reserved.
PY - 2019/1
Y1 - 2019/1
N2 - 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.
AB - 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.
KW - Animals
KW - Behavior, Animal/drug effects
KW - Brain/drug effects
KW - Disease Models, Animal
KW - Disease Progression
KW - Epileptic Syndromes/drug therapy
KW - Male
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Mitochondria/drug effects
KW - Phosphorylation/drug effects
KW - Piperazines/pharmacology
KW - Prepulse Inhibition/drug effects
KW - Protein-Serine-Threonine Kinases/deficiency
KW - Random Allocation
KW - Receptors, Serotonin/metabolism
KW - Serotonin Receptor Agonists/pharmacology
KW - Spasms, Infantile/drug therapy
U2 - 10.1016/j.neuropharm.2018.10.018
DO - 10.1016/j.neuropharm.2018.10.018
M3 - Article
C2 - 30326240
VL - 144
SP - 104
EP - 114
JO - Neuropharmacology
JF - Neuropharmacology
SN - 0028-3908
ER -