Neuroglial Interactions in Cerebral Physiology and Pathologies, Center for Interdisciplinary Research in Biology, Collège de France, CNRS, INSERM, Labex Memolife, Université PSL, Paris, France.
Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Nat Commun. 2024 Apr 27;15(1):3583. doi: 10.1038/s41467-024-47681-y.
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.
脆性 X 综合征（FXS）是一种遗传性智力障碍，由 mRNA 结合的脆性 X 智力迟钝蛋白（FMRP）缺失引起。FXS 的特征是神经元过度兴奋和行为缺陷，但这些关键功能障碍的机制仍不清楚。在这里，我们使用 FXS 的雄性 Fmr1 基因敲除小鼠模型，发现了异常的细胞外钾离子稳态，以及星形胶质细胞中钾离子通道 Kir4.1 表达和功能受损。此外，我们揭示了 Kir4.1 mRNA 是 FMRP 的结合靶标。最后，我们表明，星形胶质细胞 Kir4.1 的缺陷是 Fmr1 基因敲除小鼠神经元过度兴奋和几种行为缺陷的基础。从 Fmr1 基因敲除小鼠的海马星形胶质细胞中特异性递送 Kir4.1 通道，确实可以挽救正常的星形胶质细胞钾离子摄取、神经元兴奋性以及认知和社交能力。我们的发现揭示了星形胶质细胞功能障碍在 FXS 病理生理学中的重要作用，并确定 Kir4.1 通道是 FXS 的潜在治疗靶点。
