Hyperexcitability of Sensory Neurons in Fragile X Mouse Model

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.

Fragile X Mental Retardation Protein (FMRP) expression in human nociceptor axons of the spinal dorsal horn— Implications for RNA targeting and localized translation

“…This is consistent with its binding and modulation of ion channels in the axonal plasma membrane (Brager & Johnston, 2014; Contractor, 2013; P.-Y. Deng et al, 2013, 2019, 2021; Ferron, 2016; Ferron et al, 2020b). In DRG neuron terminals, it directly binds Cav2.2 to regulate synaptic vesicle exocytosis (Ferron, 2016; Ferron et al, 2014, 2020b).…”

“…Zhang et al, 2012). In DRG neurons, it binds ion channels to regulate synaptic vesicle exocytosis and modulates their presence in the plasma membrane to regulate excitability (P.-Y. Deng et al, 2021; Ferron et al, 2014; Ferron, 2016; Ferron et al, 2020a).…”

“…In rodents, FMRP regulates DRG neuron excitability and long-term plasticity including in chronic pain models (Asiedu et al, 2011; P.-Y. Deng et al, 2021; Ferron et al, 2014; Ferron, 2016; Ferron et al, 2020a; Price et al, 2007). FMR1 null mice exhibit decreased acute nociceptive sensitization, reduced inflammation-induced hyperalgesia, and delayed SNI-induced mechanical allodynia (Asiedu et al, 2011; Price et al, 2007).…”

“…Evidence from rodent models suggests that the likely site of action is the DRG or spinal cord (Asiedu et al, 2011; P.-Y. Deng et al, 2021; Ferron et al, 2020a; Mei et al, 2020; Price et al, 2006, 2007; Ramírez-López et al, 2021; Y. Yang et al, 2021).…”

Daily membrane capacitance changes in mouse neurons

“…It is common practice to report changes in capacitance as a proxy for changes in membrane surface (Haedo and Golowasch 2006;Perez-Garcia et al 2021;Pineda et al 2008;Royeck et al 2008). In juveniles and adults, however, altered capacitance has only being reported for some mouse models of some neurological conditions or after traumatic insult (Adamsky et al ;Akopian et al 2016;Deng et al 2021;Perez et al 2021;Rangel-Barajas et al 2021;Tewari et al 2018). Indeed, after maturation is completed, membrane capacitance is largely considered to be a non-regulated, constant biophysical property of the neurons (however see (Scott et al 2022)), since membrane [1] A C d  = 3 thickness (d) and the properties of membrane lipids, captured by the dielectric constant (), are also thought to be stable (Gentet et al 2000).…”