Astroglial Kir4.1 potassium channel deficit drives neuronal hyperexcitability and behavioral defects in Fragile X syndrome mouse model

Nat Commun. 2024 Apr 27;15(1):3583. doi: 10.1038/s41467-024-47681-y.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Astrocytes* / metabolism
  • Behavior, Animal
  • Disease Models, Animal
  • Fragile X Mental Retardation Protein* / genetics
  • Fragile X Mental Retardation Protein* / metabolism
  • Fragile X Syndrome* / genetics
  • Fragile X Syndrome* / metabolism
  • Fragile X Syndrome* / physiopathology
  • Hippocampus / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons* / metabolism
  • Neurons* / physiology
  • Potassium / metabolism
  • Potassium Channels, Inwardly Rectifying* / genetics
  • Potassium Channels, Inwardly Rectifying* / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism

Substances

  • Fmr1 protein, mouse
  • Fragile X Mental Retardation Protein
  • Kcnj10 (channel)
  • Potassium
  • Potassium Channels, Inwardly Rectifying
  • RNA, Messenger