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Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice

Abstract

Sensory perturbations in visual, auditory and tactile perception are core problems in fragile X syndrome (FXS). In the Fmr1 knockout mouse model of FXS, the maturation of synapses and circuits during critical period (CP) development in the somatosensory cortex is delayed, but it is unclear how this contributes to altered tactile sensory processing in the mature CNS. Here we demonstrate that inhibiting the juvenile chloride co-transporter NKCC1, which contributes to altered chloride homeostasis in developing cortical neurons of FXS mice, rectifies the chloride imbalance in layer IV somatosensory cortex neurons and corrects the development of thalamocortical excitatory synapses during the CP. Comparison of protein abundances demonstrated that NKCC1 inhibition during early development caused a broad remodeling of the proteome in the barrel cortex. In addition, the abnormally large size of whisker-evoked cortical maps in adult Fmr1 knockout mice was corrected by rectifying the chloride imbalance during the early CP. These data demonstrate that correcting the disrupted driving force through GABAA receptors during the CP in cortical neurons restores their synaptic development, has an unexpectedly large effect on differentially expressed proteins, and produces a long-lasting correction of somatosensory circuit function in FXS mice.

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Acknowledgements

We thank Dr. Máté Marosi for help with the intrinsic signal imaging experiments. This work was funded by grants from NIH/NIMH (1R21MH104808) to AC, DOD USAMRMC W81XWH-14-1-0433 and a John Merck Fund award to AC and CP-C, the Simons Foundation (SFARI Award 295438) and NIH/NICHD (5R01HD054453) to CP-C. JNS was supported by NIH/NIDCD (R00DC-013805) and The Hartwell Foundation. QH was supported by a fellowship from the FRAXA Research Foundation. Data from LC-MS experiments were uploaded to a public repository ftp://MSV000081526@massive.ucsd.edu

Author contributions

QH, EA, SNS, CP performed experiments, analyzed data, and contributed to writing of the manuscript. JNS, CP-C and AC provided direction for the study, analyzed data, and wrote the manuscript. CP-C and AC generated funding to support the experiments. All authors contributed to the conception and design of the experiments.

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Correspondence to Anis Contractor.

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He, Q., Arroyo, E.D., Smukowski, S.N. et al. Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice. Mol Psychiatry 24, 1732–1747 (2019). https://doi.org/10.1038/s41380-018-0048-y

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