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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 to 25% of individuals with FXS.However,no overall increased excitability has been reported in fmrl knockout (KO) mice,except for increased sensitivity to auditory stimulation.We examined here the influence of seizure activity on the expression of fmr1 mRNA and protein (FMRP) in the forebrain,and the role of FMRP in the kindling model of limbic epileptogenesis.We found that kindling increased the levels of fmr1 mRNA and protein in an activity-dependent manner in the wild-type mice.The development of kindling was dramatically accelerated in the fmr1 KO mice.Furthermore,the fmr1 KO mice displayed prolonged electrographic seizures during kindling and more severe mossy fiber sprouting after fully kindled.Our data revealed that FMRP plays a critical role in activity-dependent regulation of neuronal excitability and limbic epileptogenesis.