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 journalArticle

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

Fingerprint

Cyclin-Dependent Kinase 5
Pharmacology
Brain
Ribosomal Protein S6 Kinases
Phenotype
Behavioral Symptoms
Neuronal Plasticity
Morphogenesis
Mitochondria
Phosphotransferases
Phosphorylation
Mutation
Prepulse Inhibition
serotonin 7 receptor
Genes
Proteins

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 journalArticle

Vigli, D, Rusconi, L, Valenti, D, La Montanara, P, Cosentino, L, Lacivita, E, Leopoldo, M, Amendola, E, Gross, C, Landsberger, N, Laviola, G, Kilstrup-Nielsen, C, Vacca, RA & De Filippis, B 2019, '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', Neuropharmacology, vol. 144, pp. 104-114. https://doi.org/10.1016/j.neuropharm.2018.10.018
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. / 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. In: Neuropharmacology. 2019 ; Vol. 144. pp. 104-114.
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title = "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",
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.",
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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

VL - 144

SP - 104

EP - 114

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -