Abstract
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 Fmr1 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 Fmr1 KO compared to WT. A selective HCN channel blocker abolished differences in all measures of sensory neuron excitability between WT and Fmr1 KO neurons. These results reveal a hyperexcitable state of peripheral sensory neurons in Fmr1 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.
Highlights
Fragile X syndrome (FXS) is the leading monogenetic cause of intellectual disability (ID) and autism
We found that most of the small/medium diameter neurons [mean diameter: 19.14 ± 0.53 μm (WT), 19.84 ± 0.54 μm (KO)] in the short-term dorsal root ganglia (DRG) cultures exhibit tonic action potential (AP) firing, whereas all tested large neurons (>30 μm) show phasic AP firing
We found a hyperexcitable state of peripheral sensory neurons characterized by markedly increased AP frequency and reduced threshold caused by loss of Fragile X Mental Retardation Protein (FMRP)
Summary
Fragile X syndrome (FXS) is the leading monogenetic cause of intellectual disability (ID) and autism. This disorder most commonly results from transcriptional silencing of the Fmr gene causing loss of expression of Fragile X Mental Retardation Protein (FMRP) (Penagarikano et al, 2007). Individuals with FXS typically present with cognitive dysfunction, learning deficits, social and behavioral problems, neurological deficits, and morphological abnormalities. Among most prevalent FXS deficits is hypersensitivity to sensory stimuli, including auditory, visual, and tactile stimuli. Individuals with FXS commonly exhibit somatosensory deficits, such as hypersensitivity to touch (Cascio, 2010), Self-injurious behaviors in Fragile X individuals
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
