The NKCC1 Inhibitor Bumetanide Restores Cortical Feedforward Inhibition and Lessens Sensory Hypersensitivity in Early Postnatal Fragile X Mice

Nazim Kourdougli, Toshihiro Nomura, Michelle W. Wu, Anouk Heuvelmans, Zoë Dobler, Anis Contractor, Carlos Portera-Cailliau*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)507-516
Number of pages10
JournalBiological psychiatry
Volume97
Issue number5
DOIs
StateAccepted/In press - 2024

Funding

The authors thank Anand Suresh for ideas and suggestions throughout the project and John Armstrong for help with bumetanide injections. This work was supported by the following grants: R01NS117597 (NIH-NINDS) and R01HD054453 (NIH-NICHD) awarded to C.P.-C., Department of Defense (DOD, 13196175) awarded to C.P-C and A.C., R01HD108370 (NIH-NICHD) awarded to C.P-C and A.C., a grant from the FRAXA foundation awarded to N.K., Madeline Julie Vervoort Fund (Amsterdam University, #7682) to A.H, and the T32 UCLA-Caltech MSTP to M.W. No preprint version of this manuscript was made available on Biorxiv prior to publication in Biological Psychiatry. This work was supported by National Institutes of Health (NIH)-National Institute of Neurological Disorders and Stroke (Grant No. R01NS117597 [to CP-C]), NIH-National Institute of Child Health and Human Development (Grant No. R01HD054453 [to CP-C]), Department of Defense (Grant No. 13196175 [to CP-C and AC]), NIH-National Institute of Child Health and Human Development (Grant No. R01HD108370 [to CP-C and AC]), the FRAXA foundation (to NK), Madeline Julie Vervoort Fund (Amsterdam University, Grant No. 7682 [to AH]), and the T32 UCLA-Caltech Medical Scientist Training Program from NIH-National Institute of General Medical Sciences (Grant No. T32GM008042). We thank Anand Suresh for ideas and suggestions throughout the project and John Armstrong for help with bumetanide injections. The authors report no biomedical financial interests or potential conflicts of interest.

Keywords

  • Autism spectrum disorders
  • Fragile X syndrome
  • In vivo calcium imaging
  • Interneuron
  • NKCC1
  • Somatosensory cortex

ASJC Scopus subject areas

  • Biological Psychiatry

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