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Cerebral Cortex Advance Access published online on October 1, 2008
Cerebral Cortex, doi:10.1093/cercor/bhn163
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© 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.

Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome

Li-Feng Qiu1, Ting-Jia Lu1, Xiao-Ling Hu1, Yong-Hong Yi2, Wei-Ping Liao2 and Zhi-Qi Xiong1

1 Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, 2 Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Guangzhou 510260, China

Address correspondence to Dr Zhi-Qi Xiong, Institute of Neuroscience, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China. Email: xiongzhiqi{at}ion.ac.cn.

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.

Key Words: epilepsy • FMRP • kindling • mGluR5 • mossy fiber sprouting • NMDA


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