AUTHOR=Deng Pan-Yue , Avraham Oshri , Cavalli Valeria , Klyachko Vitaly A. 

TITLE=Hyperexcitability of Sensory Neurons in Fragile X Mouse Model

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=14

YEAR=2021

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2021.796053

DOI=10.3389/fnmol.2021.796053

ISSN=1662-5099

ABSTRACT=<p>Sensory hypersensitivity and somatosensory deficits represent the core symptoms of Fragile X syndrome (FXS). These alterations are believed to arise from changes in cortical sensory processing, while potential deficits in the function of peripheral sensory neurons residing in dorsal root ganglia remain unexplored. We found that peripheral sensory neurons exhibit pronounced hyperexcitability in <italic>Fmr1</italic> KO mice, manifested by markedly increased action potential (AP) firing rate and decreased threshold. Unlike excitability changes found in many central neurons, no significant changes were observed in AP rising and falling time, peak potential, amplitude, or duration. Sensory neuron hyperexcitability was caused primarily by increased input resistance, without changes in cell capacitance or resting membrane potential. Analyses of the underlying mechanisms revealed reduced activity of HCN channels and reduced expression of HCN1 and HCN4 in <italic>Fmr1</italic> KO compared to WT. A selective HCN channel blocker abolished differences in all measures of sensory neuron excitability between WT and <italic>Fmr1</italic> KO neurons. These results reveal a hyperexcitable state of peripheral sensory neurons in <italic>Fmr1</italic> KO mice caused by dysfunction of HCN channels. In addition to the intrinsic neuronal dysfunction, the accompanying paper examines deficits in sensory neuron association/communication with their enveloping satellite glial cells, suggesting contributions from both neuronal intrinsic and extrinsic mechanisms to sensory dysfunction in the FXS mouse model.</p>