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 BK_Ca channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BK_Ca channels. Our results provide strong evidence pointing to the utility of BK_Ca channel openers for the treatment of the sensory hypersensitivity aspects of FXS. [ABSTRACT FROM AUTHOR]