Effects of chronic inhibition of phosphodiesterase-4D on behavior and regional rates of cerebral protein synthesis in a mouse model of fragile X syndrome.
Neurobiol Dis
; 159: 105485, 2021 11.
Article
en En
| MEDLINE
| ID: mdl-34411704
ABSTRACT
Fragile X Syndrome (FXS) is caused by silencing the FMR1 gene which results in intellectual disability, hyperactivity, sensory hypersensitivity, autistic-like behavior, and susceptibility to seizures. This X-linked disorder is also associated with reduced cAMP levels in humans as well as animal models. We assessed the therapeutic and neurochemical effects of chronic administration of the phosphodiesterase-4D negative allosteric modulator, BPN14770, in a mouse model of FXS (Fmr1 KO). Groups of male Fmr1 KO mice and control littermates were treated with dietary BPN14770 commencing postnatal day 21. A dose-response effect was investigated. At 90 days of age, mice underwent behavior tests including open field, novel object recognition, three chambered sociability and social novelty tests, passive avoidance, and sleep duration analysis. These tests were followed by in vivo measurement of regional rates of cerebral protein synthesis (rCPS) with the autoradiographic L-[1-14C]leucine method. BPN14770 treatment had positive effects on the behavioral phenotype in Fmr1 KO mice. Some effects such as increased sleep duration and increased social behavior occurred in both genotypes. In the open field, the hyperactivity response in Fmr1 KO mice was ameliorated by BPN14770 treatment at low and intermediate doses. BPN14770 treatment tended to increase rCPS in a dose-dependent manner in WT mice, whereas in Fmr1 KO mice effects on rCPS were less apparent. Results indicate BPN14770 treatment improves some behavior in Fmr1 KO mice. Results also suggest a genotype difference in the regulation of translation via a cAMP-dependent pathway.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Sueño
/
Biosíntesis de Proteínas
/
Conducta Animal
/
Cerebro
/
Inhibidores de Fosfodiesterasa 4
/
Síndrome del Cromosoma X Frágil
Límite:
Animals
Idioma:
En
Revista:
Neurobiol Dis
Asunto de la revista:
NEUROLOGIA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos