Cargando…

Hyperexcitability of Sensory Neurons in Fragile X Mouse Model

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 rem...

Descripción completa

Detalles Bibliográficos
Autores principales: Deng, Pan-Yue, Avraham, Oshri, Cavalli, Valeria, Klyachko, Vitaly A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8727524/
https://www.ncbi.nlm.nih.gov/pubmed/35002623
http://dx.doi.org/10.3389/fnmol.2021.796053
_version_ 1784626546423627776
author Deng, Pan-Yue
Avraham, Oshri
Cavalli, Valeria
Klyachko, Vitaly A.
author_facet Deng, Pan-Yue
Avraham, Oshri
Cavalli, Valeria
Klyachko, Vitaly A.
author_sort Deng, Pan-Yue
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8727524
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-87275242022-01-06 Hyperexcitability of Sensory Neurons in Fragile X Mouse Model Deng, Pan-Yue Avraham, Oshri Cavalli, Valeria Klyachko, Vitaly A. Front Mol Neurosci Neuroscience 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. Frontiers Media S.A. 2021-12-22 /pmc/articles/PMC8727524/ /pubmed/35002623 http://dx.doi.org/10.3389/fnmol.2021.796053 Text en Copyright © 2021 Deng, Avraham, Cavalli and Klyachko. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Deng, Pan-Yue
Avraham, Oshri
Cavalli, Valeria
Klyachko, Vitaly A.
Hyperexcitability of Sensory Neurons in Fragile X Mouse Model
title Hyperexcitability of Sensory Neurons in Fragile X Mouse Model
title_full Hyperexcitability of Sensory Neurons in Fragile X Mouse Model
title_fullStr Hyperexcitability of Sensory Neurons in Fragile X Mouse Model
title_full_unstemmed Hyperexcitability of Sensory Neurons in Fragile X Mouse Model
title_short Hyperexcitability of Sensory Neurons in Fragile X Mouse Model
title_sort hyperexcitability of sensory neurons in fragile x mouse model
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8727524/
https://www.ncbi.nlm.nih.gov/pubmed/35002623
http://dx.doi.org/10.3389/fnmol.2021.796053
work_keys_str_mv AT dengpanyue hyperexcitabilityofsensoryneuronsinfragilexmousemodel
AT avrahamoshri hyperexcitabilityofsensoryneuronsinfragilexmousemodel
AT cavallivaleria hyperexcitabilityofsensoryneuronsinfragilexmousemodel
AT klyachkovitalya hyperexcitabilityofsensoryneuronsinfragilexmousemodel