Kourdougli Nazim, Nomura Toshihiro, Wu Michelle W, Heuvelmans Anouk, Dobler Zoë, Contractor Anis, Portera-Cailliau Carlos
Department of Neurology, University of California, Los Angeles, Los Angeles, California.
Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
Biol Psychiatry. 2025 Mar 1;97(5):507-516. doi: 10.1016/j.biopsych.2024.06.023. Epub 2024 Jun 29.
Exaggerated responses to sensory stimuli, a hallmark of fragile X syndrome, contribute to anxiety and learning challenges. Sensory hypersensitivity is recapitulated in the Fmr1 knockout (KO) mouse model of fragile X syndrome. Recent studies in Fmr1 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 Fmr1 KO mice. However, it remains unknown whether bumetanide can rescue earlier circuit phenotypes or sensory hypersensitivity in Fmr1 KO mice.
We used acute and chronic systemic administration of bumetanide in Fmr1 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 Fmr1 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 Fmr1 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 Fmr1 KO can be mitigated by inhibitors of NKCC1, such as the Food and Drug Administration-approved diuretic bumetanide.
对感觉刺激的过度反应是脆性X综合征的一个标志，会导致焦虑和学习障碍。脆性X综合征的Fmr1基因敲除（KO）小鼠模型再现了感觉超敏反应。最近对Fmr1基因敲除小鼠的研究表明，皮质中间神经元的活动存在差异，并且在发育过程中GABA（γ-氨基丁酸）信号的极性转换延迟。此前，我们报道用利尿剂布美他尼阻断氯离子转运体NKCC1可以挽救Fmr1基因敲除小鼠初级体感皮层（S1）的突触回路表型。然而，布美他尼是否能挽救Fmr1基因敲除小鼠早期的回路表型或感觉超敏反应仍不清楚。
我们对Fmr1基因敲除小鼠进行了布美他尼的急性和慢性全身给药，并进行了体内双光子钙成像以记录神经元活动，同时用高分辨率视频跟踪小鼠行为。
我们证明，与野生型对照相比，Fmr1基因敲除小鼠S1区第2/3层锥体神经元在出生后第6天表现出更高频率的同步事件。急性给予布美他尼可逆转这种情况。此外，慢性布美他尼治疗（出生后第5 - 14天）恢复了Fmr1基因敲除小鼠S1区的回路差异，包括减少神经元对重复触须刺激的适应性，并改善了触觉防御性。布美他尼治疗还纠正了S1区第2/3层神经元前馈抑制的降低，并增强了小白蛋白中间神经元的回路参与度。
这进一步支持了这样一种观点，即Fmr1基因敲除小鼠的突触、回路和感觉行为表型可以被NKCC1抑制剂（如美国食品药品监督管理局批准的利尿剂布美他尼）减轻。
