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 behavioral 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 neurobehavioral phenotype of 1-year-old Cdkl5- 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- male mice. In particular, LP-211 treatment completely normalizes the prepulse inhibition defects observed in Cdkl5- 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- mouse brains that can be restored by pharmacological stimulation of brain 5-HT7R.

Autore Pugliese

• Valenti Daniela , Vacca Rosa Anna

Tutti gli autori

• 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 R.A.; De Filippis B.

Titolo volume/Rivista

Neuropharmacology

Anno di pubblicazione

2019

ISSN

0028-3908

ISBN

Non Disponibile

Numero di citazioni Wos

Nessuna citazione

Ultimo Aggiornamento Citazioni

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Numero di citazioni Scopus

Non Disponibile

Ultimo Aggiornamento Citazioni

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Settori ERC

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Codici ASJC

Non Disponibile