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 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.
Qiu
Li-Feng
LF
Institute of Neuroscience and State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, China.
Lu
Ting-Jia
TJ
Hu
Xiao-Ling
XL
Yi
Yong-Hong
YH
Liao
Wei-Ping
WP
Xiong
Zhi-Qi
ZQ
D000818:Animals; D004195:Disease Models, Animal; D004827:Epilepsy / Q000503:physiopathology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000378:metabolism*; D005600:Fragile X Syndrome / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D008032:Limbic System / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout
D051860:Fragile X Messenger Ribonucleoprotein 1; C497684:Fmr1 protein, mouse