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.
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 / D. Vigli, L. Rusconi, D. Valenti, P. La Montanara, L. Cosentino, E. Lacivita, M. Leopoldo, E. Amendola, C. Gross, N. Landsberger, G. Laviola, C. Kilstrup-Nielsen, R.A. Vacca, B. De Filippis. - In: NEUROPHARMACOLOGY. - ISSN 0028-3908. - 144(2019), pp. 104-114.
|Titolo:||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|
|Parole Chiave:||Ribosomal-protein S6; fragile-X-syndrome; 5-HT7 receptor; rett-syndrome; femal mice; synaptic plasticity; nervous-system; animal-models; in-vivo; schizophrenia|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Data di pubblicazione:||2019|
|Data ahead of print / Data di stampa:||13-ott-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.neuropharm.2018.10.018|
|Appare nelle tipologie:||01 - Articolo su periodico|