Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice.

Yu Zhang, Audrey Bonnan, Guillaume Bony, Isabelle Ferezou, Susanna Pietropaolo, Melanie Ginger, Nathalie Sans, Jean Rossier, Ben Oostra, Gwen LeMasson, Andreas Frick
Nat Neurosci. 2014-11-10; 17(12): 1701-1709
DOI: 10.1038/nn.3864

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Zhang Y(1), Bonnan A(1), Bony G(1), Ferezou I(2), Pietropaolo S(3), Ginger M(1), Sans N(1), Rossier J(2), Oostra B(4), LeMasson G(1), Frick A(1).

Author information:
(1)1] INSERM, Neurocentre Magendie, Physiopathologie de la plasticité neuronale,
U862, Bordeaux, France. [2] University of Bordeaux, Neurocentre Magendie,
Physiopathologie de la plasticité neuronale, U862, Bordeaux, France.
(2)Laboratoire de Neurobiologie, ESPCI ParisTech CNRS UMR 7637, Paris, France.
(3)1] University of Bordeaux, INCIA, Talence, France. [2] CNRS, INCIA, UMR 5287,
Talence, France.
(4)Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.

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.


Auteurs Bordeaux Neurocampus