Astroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model.
Nat Commun
; 15(1): 3583, 2024 Apr 27.
Article
em En
| MEDLINE
| ID: mdl-38678030
ABSTRACT
Fragile X syndrome (FXS) is an inherited form of intellectual disability caused by the loss of the mRNA-binding fragile X mental retardation protein (FMRP). FXS is characterized by neuronal hyperexcitability and behavioral defects, however the mechanisms underlying these critical dysfunctions remain unclear. Here, using male Fmr1 knockout mouse model of FXS, we identify abnormal extracellular potassium homeostasis, along with impaired potassium channel Kir4.1 expression and function in astrocytes. Further, we reveal that Kir4.1 mRNA is a binding target of FMRP. Finally, we show that the deficit in astroglial Kir4.1 underlies neuronal hyperexcitability and several behavioral defects in Fmr1 knockout mice. Viral delivery of Kir4.1 channels specifically to hippocampal astrocytes from Fmr1 knockout mice indeed rescues normal astrocyte potassium uptake, neuronal excitability, and cognitive and social performance. Our findings uncover an important role for astrocyte dysfunction in the pathophysiology of FXS, and identify Kir4.1 channel as a potential therapeutic target for FXS.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Astrócitos
/
Canais de Potássio Corretores do Fluxo de Internalização
/
Proteína do X Frágil da Deficiência Intelectual
/
Síndrome do Cromossomo X Frágil
/
Neurônios
Limite:
Animals
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
França