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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Molecular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fnmol.2021.796053/full |
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| author | Pan-Yue Deng Oshri Avraham Valeria Cavalli Valeria Cavalli Valeria Cavalli Vitaly A. Klyachko Vitaly A. Klyachko |
| author_facet | Pan-Yue Deng Oshri Avraham Valeria Cavalli Valeria Cavalli Valeria Cavalli Vitaly A. Klyachko Vitaly A. Klyachko |
| author_sort | Pan-Yue Deng |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-24T11:15:36Z |
| format | Article |
| id | doaj.art-3b40e83211b94b5aa5f73209ab6183d1 |
| institution | Directory Open Access Journal |
| issn | 1662-5099 |
| language | English |
| last_indexed | 2024-12-24T11:15:36Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Neuroscience |
| spelling | doaj.art-3b40e83211b94b5aa5f73209ab6183d12022-12-21T16:58:23ZengFrontiers Media S.A.Frontiers in Molecular Neuroscience1662-50992021-12-011410.3389/fnmol.2021.796053796053Hyperexcitability of Sensory Neurons in Fragile X Mouse ModelPan-Yue Deng0Oshri Avraham1Valeria Cavalli2Valeria Cavalli3Valeria Cavalli4Vitaly A. Klyachko5Vitaly A. Klyachko6Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United StatesDepartment of Neuroscience, Washington University School of Medicine, St. Louis, MO, United StatesDepartment of Neuroscience, Washington University School of Medicine, St. Louis, MO, United StatesHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United StatesCenter of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United StatesDepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United StatesHope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United StatesSensory 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.https://www.frontiersin.org/articles/10.3389/fnmol.2021.796053/fullhyperexcitabilityFragile X syndromeaction potentialsensory neuronHCN channel |
| spellingShingle | Pan-Yue Deng Oshri Avraham Valeria Cavalli Valeria Cavalli Valeria Cavalli Vitaly A. Klyachko Vitaly A. Klyachko Hyperexcitability of Sensory Neurons in Fragile X Mouse Model Frontiers in Molecular Neuroscience hyperexcitability Fragile X syndrome action potential sensory neuron HCN channel |
| 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 | hyperexcitability Fragile X syndrome action potential sensory neuron HCN channel |
| url | https://www.frontiersin.org/articles/10.3389/fnmol.2021.796053/full |
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