The NKCC1 Inhibitor Bumetanide Restores Cortical Feedforward Inhibition and Lessens Sensory Hypersensitivity in Early...

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.