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Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice

Nature Neuroscience volume 17, pages 17011709 (2014) | Download Citation

Abstract

Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1/y mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.

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Acknowledgements

We thank B. Sakmann, P. Seeburg, the Max Planck Society and the Deutsche Forschungsgemeinschaft for initial support of this study. We thank J.-C. Delpech, S. Dos Santos Carvalho and W. Crusio for technical and scientific advice. Some data was acquired using equipment of the Bordeaux Imaging Center, the ESPCI ParisTech and Biochemistry Facility of the Bordeaux Neurocampus. This research was funded by FRAXA Research Foundation, INSERM, CNRS, Conseil de la Region d'Aquitaine, Fondation Jérôme Lejeune, Fédération pour la Recherche sur le Cerveau, Fondation pour la Recherche Médicale (SPF20130526794) and Labex-BRAIN (ANR-10-LABEX-43).

Author information

Author notes

    • Yu Zhang
    • , Audrey Bonnan
    • , Isabelle Ferezou
    •  & Jean Rossier

    Present address: Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK (Y.Z.), Max Planck Florida Institute for Neuroscience, Jupiter, Florida, USA (A.B.), Unité de Neurosciences Information et Complexité, CNRS UPR 3293, Gif-sur-Yvette, France (I.F.), Centre de Psychiatrie et Neurosciences, INSERM U894, Université Paris Descartes, Paris, France (J.R.).

    • Yu Zhang
    • , Audrey Bonnan
    •  & Guillaume Bony

    These authors contributed equally to this work.

Affiliations

  1. INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U862, Bordeaux, France.

    • Yu Zhang
    • , Audrey Bonnan
    • , Guillaume Bony
    • , Melanie Ginger
    • , Nathalie Sans
    • , Gwen LeMasson
    •  & Andreas Frick
  2. University of Bordeaux, Neurocentre Magendie, Physiopathologie de la plasticité neuronale, U862, Bordeaux, France.

    • Yu Zhang
    • , Audrey Bonnan
    • , Guillaume Bony
    • , Melanie Ginger
    • , Nathalie Sans
    • , Gwen LeMasson
    •  & Andreas Frick
  3. Laboratoire de Neurobiologie, ESPCI ParisTech CNRS UMR 7637, Paris, France.

    • Isabelle Ferezou
    •  & Jean Rossier
  4. University of Bordeaux, INCIA, Talence, France.

    • Susanna Pietropaolo
  5. CNRS, INCIA, UMR 5287, Talence, France.

    • Susanna Pietropaolo
  6. Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.

    • Ben Oostra

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Contributions

A.F. conceived the project. Y.Z. and A.B. collected the in vitro electrophysiological and calcium imaging data. G.B. carried out the in vivo electrophysiological experiments. A.B. and N.S. performed the western blot experiments. I.F. performed the VSD imaging experiments. S.P. and M.G. carried out the behavioral experiments. G.L. collected the NEURON modeling data. B.O. provided the second-generation Fmr1/y mouse line. J.R. assisted in data interpretation. A.F., M.G., A.B., Y.Z., G.B. and I.F. wrote the paper and all of the other authors provided feedback.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Andreas Frick.

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DOI

https://doi.org/10.1038/nn.3864

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