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Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome

Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20–25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sens...

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Autores principales: Qiu, Li-Feng, Lu, Ting-Jia, Hu, Xiao-Ling, Yi, Yong-Hong, Liao, Wei-Ping, Xiong, Zhi-Qi
Formato: Texto
Lenguaje:English
Publicado: Oxford University Press 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693616/
https://www.ncbi.nlm.nih.gov/pubmed/18832330
http://dx.doi.org/10.1093/cercor/bhn163
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author Qiu, Li-Feng
Lu, Ting-Jia
Hu, Xiao-Ling
Yi, Yong-Hong
Liao, Wei-Ping
Xiong, Zhi-Qi
author_facet Qiu, Li-Feng
Lu, Ting-Jia
Hu, Xiao-Ling
Yi, Yong-Hong
Liao, Wei-Ping
Xiong, Zhi-Qi
author_sort Qiu, Li-Feng
collection PubMed
description Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20–25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sensitivity to auditory stimulation. Here, we report that kindling increased the expressions of Fmr1 mRNA and protein in the forebrain of wild-type (WT) mice. Kindling development was dramatically accelerated in Fmr1 KO mice, and Fmr1 KO mice also displayed prolonged electrographic seizures during kindling and more severe mossy fiber sprouting after kindling. The accelerated rate of kindling was partially repressed by inhibiting N-methyl-D-aspartic acid receptor (NMDAR) with MK-801 or mGluR5 receptor with 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The rate of kindling development in WT was not effected by MPEP, however, suggesting that FMRP normally suppresses epileptogenic signaling downstream of metabolic glutamate receptors. Our findings reveal that FMRP plays a critical role in suppressing limbic epileptogenesis and predict that the enhanced susceptibility of patients with FXS to epilepsy is a direct consequence of the loss of an important homeostatic factor that mitigates vulnerability to excessive neuronal excitation.
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spelling pubmed-26936162009-06-09 Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome Qiu, Li-Feng Lu, Ting-Jia Hu, Xiao-Ling Yi, Yong-Hong Liao, Wei-Ping Xiong, Zhi-Qi Cereb Cortex Articles Fragile X syndrome (FXS), caused by silencing of the Fmr1 gene, is the most common form of inherited mental retardation. Epilepsy is reported to occur in 20–25% of individuals with FXS. However, no overall increased excitability has been reported in Fmr1 knockout (KO) mice, except for increased sensitivity to auditory stimulation. Here, we report that kindling increased the expressions of Fmr1 mRNA and protein in the forebrain of wild-type (WT) mice. Kindling development was dramatically accelerated in Fmr1 KO mice, and Fmr1 KO mice also displayed prolonged electrographic seizures during kindling and more severe mossy fiber sprouting after kindling. The accelerated rate of kindling was partially repressed by inhibiting N-methyl-D-aspartic acid receptor (NMDAR) with MK-801 or mGluR5 receptor with 2-methyl-6-(phenylethynyl)-pyridine (MPEP). The rate of kindling development in WT was not effected by MPEP, however, suggesting that FMRP normally suppresses epileptogenic signaling downstream of metabolic glutamate receptors. Our findings reveal that FMRP plays a critical role in suppressing limbic epileptogenesis and predict that the enhanced susceptibility of patients with FXS to epilepsy is a direct consequence of the loss of an important homeostatic factor that mitigates vulnerability to excessive neuronal excitation. Oxford University Press 2009-07 2008-10-01 /pmc/articles/PMC2693616/ /pubmed/18832330 http://dx.doi.org/10.1093/cercor/bhn163 Text en © 2008 The Authors This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Qiu, Li-Feng
Lu, Ting-Jia
Hu, Xiao-Ling
Yi, Yong-Hong
Liao, Wei-Ping
Xiong, Zhi-Qi
Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome
title Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome
title_full Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome
title_fullStr Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome
title_full_unstemmed Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome
title_short Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome
title_sort limbic epileptogenesis in a mouse model of fragile x syndrome
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2693616/
https://www.ncbi.nlm.nih.gov/pubmed/18832330
http://dx.doi.org/10.1093/cercor/bhn163
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