Exaggerated responses to sensory stimuli, a hallmark of fragile X syndrome, contribute to anxiety and learning challenges. Sensory hypersensitivity is recapitulated in the knockout (KO) mouse model of fragile X syndrome. Recent studies in KO mice have demonstrated differences in the activity of cortical interneurons and a delayed switch in the polarity of GABA (gamma-aminobutyric acid) signaling during development. Previously, we reported that blocking the chloride transporter NKCC1 with the diuretic bumetanide could rescue synaptic circuit phenotypes in the primary somatosensory cortex (S1) of KO mice. However, it remains unknown whether bumetanide can rescue earlier circuit phenotypes or sensory hypersensitivity in KO mice. We used acute and chronic systemic administration of bumetanide in KO mice and performed in vivo 2-photon calcium imaging to record neuronal activity, while tracking mouse behavior with high-resolution videos. We demonstrated that layer 2/3 pyramidal neurons in the S1 of KO mice showed a higher frequency of synchronous events on postnatal day 6 than wild-type controls. This was reversed by acute administration of bumetanide. Furthermore, chronic bumetanide treatment (postnatal days 5–14) restored S1 circuit differences in KO mice, including reduced neuronal adaptation to repetitive whisker stimulation, and ameliorated tactile defensiveness. Bumetanide treatment also rectified the reduced feedforward inhibition of layer 2/3 neurons in the S1 and boosted the circuit participation of parvalbumin interneurons. This further supports the notion that synaptic, circuit, and sensory behavioral phenotypes in KO can be mitigated by inhibitors of NKCC1, such as the Food and Drug Administration–approved diuretic bumetanide.

中文翻译：

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NKCC1 抑制剂布美他尼可恢复出生后早期脆性 X 小鼠的皮质前馈抑制并减轻感觉超敏反应


对感觉刺激的夸张反应是脆性 X 综合征的标志，会导致焦虑和学习挑战。感觉超敏反应在脆性 X 综合征的敲除 （KO） 小鼠模型中进行了概括。最近对 KO 小鼠的研究表明，在发育过程中皮层中间神经元活性的差异和 GABA（γ-氨基丁酸）信号转导极性的延迟切换。以前，我们报道了用利尿剂布美他尼阻断氯转运蛋白 NKCC1 可以挽救 KO 小鼠初级体感皮层 （S1） 中的突触回路表型。然而，布美他尼是否可以挽救 KO 小鼠的早期回路表型或感觉超敏反应仍未知。我们在 KO 小鼠中使用布美他尼的急性和慢性全身给药，并进行体内 2 光子钙成像以记录神经元活动，同时使用高分辨率视频跟踪小鼠行为。我们证明，KO 小鼠 S1 中的 2/3 层锥体神经元在出生后第 6 天表现出比野生型对照更高的同步事件频率。这被布美他尼的急性给药逆转。此外，慢性布美他尼治疗（出生后第 5-14 天）恢复了 KO 小鼠的 S1 回路差异，包括神经元对重复胡须刺激的适应减少，并改善了触觉防御性。布美他尼治疗还纠正了 S1 中第 2/3 层神经元的前馈抑制降低，并促进了小白蛋白中间神经元的回路参与。这进一步支持了 KO 中的突触、回路和感觉行为表型可以通过 NKCC1 抑制剂（例如美国食品和药物管理局批准的利尿剂布美他尼）来缓解的观点。