Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1(-/y) mice.
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.
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.
Yu
Y
Zhang
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.
Audrey
A
Bonnan
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.
Guillaume
G
Bony
Laboratoire de Neurobiologie, ESPCI ParisTech CNRS UMR 7637, Paris, France.
Isabelle
I
Ferezou
1] University of Bordeaux, INCIA, Talence, France. [2] CNRS, INCIA, UMR 5287, Talence, France.
Susanna
S
Pietropaolo
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.
Melanie
M
Ginger
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.
Nathalie
N
Sans
Laboratoire de Neurobiologie, ESPCI ParisTech CNRS UMR 7637, Paris, France.
Jean
J
Rossier
Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
Ben
B
Oostra
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.
Gwen
G
LeMasson
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.
Andreas
A
Frick
D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D053447:Channelopathies / Q000235:genetics / Q000503:physiopathology*; D003712:Dendrites / Q000473:pathology / Q000502:physiology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019579:Neocortex / Q000473:pathology / Q000502:physiology*; D009924:Organ Culture Techniques; D013216:Reflex, Startle / Q000502:physiology
D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse