Fragile X syndrome (FXS) is caused by suppressed expression of
fragile X mental retardation protein (FMRP), which results in
intellectual disability accompanied by many variably manifested characteristics, such as hyperactivity,
seizures and autistic-like behaviors. Treatment of mice that lack FMRP, Fmr1 knockout (KO) mice, with
lithium has been reported to ameliorate locomotor hyperactivity, prevent
hypersensitivity to audiogenic
seizures, improve passive avoidance behavior and attenuate sociability deficits. To focus on the defining characteristic of FXS, which is
cognitive impairment, we tested if
lithium treatment ameliorated impairments in four cognitive tasks in Fmr1 KO mice, tested if the response to
lithium differed in adolescent and adult mice and tested if
therapeutic effects persisted after discontinuation of
lithium administration. Fmr1 KO mice displayed impaired cognition in the novel object detection task, temporal ordering for objects task and coordinate and categorical spatial processing tasks. Chronic
lithium treatment of adolescent (from 4 to 8 weeks of age) and adult (from 8 to 12 weeks of age) mice abolished
cognitive impairments in all four cognitive tasks. Cognitive deficits returned after
lithium treatment was discontinued for 4 weeks. These results show that Fmr1 KO mice exhibit severe impairments in these cognitive tasks, that
lithium is equally effective in normalizing cognition in these tasks whether it is administered to young or adult mice and that
lithium administration must be continued for the cognitive improvements to be sustained. These findings provide further evidence that
lithium administration may be beneficial for individuals with FXS.