Imbalanced expression of cation-chloride cotransporters as a potential therapeutic target in an Angelman syndrome mouse model.
Sci Rep
; 13(1): 5685, 2023 04 17.
Article
em En
| MEDLINE
| ID: mdl-37069177
ABSTRACT
Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the maternally expressed UBE3A gene. Treatments for the main manifestations, including cognitive dysfunction or epilepsy, are still under development. Recently, the Cl- importer Na+-K+-Cl- cotransporter 1 (NKCC1) and the Cl- exporter K+-Cl- cotransporter 2 (KCC2) have garnered attention as therapeutic targets for many neurological disorders. Dysregulation of neuronal intracellular Cl- concentration ([Cl-]i) is generally regarded as one of the mechanisms underlying neuronal dysfunction caused by imbalanced expression of these cation-chloride cotransporters (CCCs). Here, we analyzed the regulation of [Cl-]i and the effects of bumetanide, an NKCC1 inhibitor, in Angelman syndrome models (Ube3am-/p+ mice). We observed increased NKCC1 expression and decreased KCC2 expression in the hippocampi of Ube3am-/p+ mice. The average [Cl-]i of CA1 pyramidal neurons was not significantly different but demonstrated greater variance in Ube3am-/p+ mice. Tonic GABAA receptor-mediated Cl- conductance was reduced, which may have contributed to maintaining the normal average [Cl-]i. Bumetanide administration restores cognitive dysfunction in Ube3am-/p+ mice. Seizure susceptibility was also reduced regardless of the genotype. These results suggest that an imbalanced expression of CCCs is involved in the pathophysiological mechanism of Ube3am-/p+ mice, although the average [Cl-]i is not altered. The blockage of NKCC1 may be a potential therapeutic strategy for patients with Angelman syndrome.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Síndrome de Angelman
/
Simportadores
/
Epilepsia
Limite:
Animals
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Japão