Based on the insights that an ERK1/2 signaling pathway lies upstream of the excessive hippocampal protein synthesis in the Fmr1
KO (Osterweil et al., 2010
) and that lovastatin can, among other actions, inhibit Ras-ERK1/2 signaling in hippocampal neurons (Li et al., 2005
), we wondered if lovastatin could correct core biochemical and electrophysiological consequences of the loss of the translational repressor FMRP in FXS. We thought this was a particularly exciting prospect because lovastatin is widely prescribed, has a known safety profile, and is approved for use in children (to treat hypercholesterolemia). Our results show that lovastatin can indeed correct excessive protein synthesis and prevent the emergence of epileptiform activity in the Fmr1
KO hippocampus in vitro
, and can protect the Fmr1
KO mice from AGS in vivo
It has been suggested that seizures in children with developmental disorders such as FXS could worsen the progression and severity of other symptoms including autism (Berry-Kravis, 2002
; Tuchman et al., 2010
). Once manifest, seizures can be controlled with conventional anticonvulsant medications, but these drugs themselves have side effects that can exacerbate other symptoms, such as cognitive impairment. Further, prodromal changes may be as deleterious for brain development as full-blown seizures. Therefore, preventing epileptogenesis is an important goal,.
Statins have been studied previously in rodent models of epilepsy in which seizures are initiated or kindled in vivo
by administration of drugs or by direct electrical stimulation of the temporal lobes. Some studies have suggested that statins can lessen seizure activity (Lee et al., 2008
; Ramirez et al., 2011
; Xie et al., 2011
), whereas others have reported no effect (van Vliet et al., 2011
) or an exacerbation of seizures (Serbanescu et al., 2004
). Beneficial effcts have typically been attributed to reduced brain inflammation associated with seizures. In contrast to previous work, we have used a genetically engineered mouse model of FXS in which seizure phenotypes are not caused by artificial induction of inflammatory responses and neurodegeneration. Our findings point to an entirely different mechanism of action, by which lovastatin corrects multiple Fmr1
KO phenotypes including, but not limited to in vivo
seizure activity by downregulating Ras-ERK1/2 and protein synthesis.
It should be noted, however, that the connection between seizure phenotypes in the mouse model and childhood epilepsy in humans with FXS remains to be firmly established. For example, AGS may be largely a reflex event driven by activation of brainstem nuclei with limited relevance to cortical electroencephalographic seizures (Raisinghani and Faingold, 2003
). Arguing against this point of view is the observation that audio stimulation rapidly elicits (within 2 min) generalized tonic-clonic seizures in most Fmr1
KO mice, showing that hyperexcitability extends beyond brainstem neurons. Nevertheless, epileptogenesis in fragile X patients is manifest as the appearance of spontaneous seizures, which are not observed in the mouse model. The issue of whether the pathogenesis of epilepsy is shared by mice and humans lacking FMRP could be addressed if the effects of a prophylactic treatment were compared in the two species. Our findings that lovastatin, already approved for use in humans, can prevent epileptogenesis and hyperexcitability in the Fmr1
KO suggest that carefully controled human clinical trials are warranted.
As a negative regulator of the mevalonate pathway, lovastatin can impact the production of multiple compounds involved in intracellular signaling, including ubiquinone, dolichol, and isoprenoids (Goldstein and Brown, 1990
). Therefore, we cannot rule out the possibility that some beneficial effects of lovastatin could be due to actions other than the reduction in Ras-ERK1/2 signaling, including a reduction in the farnesylation of other target proteins. However, like lovastatin, inhibitors of Ras or ERK1/2 are sufficient to normalize protein synthesis, and downregulation of the ERK1/2 pathway also blocks hippocampal epileptogenesis and eliminates AGS in the Fmr1
KO (Chuang et al., 2005
; Osterweil et al., 2010
). Thus, although the precise molecular mechanisms by which lovastatin confers benefit remain to be determined, the weight of the evidence suggests that the effects are due to a reduction in Ras-ERK1/2 signaling.
This study was focused on the seizure phenotype because it has both construct (genotypic) and face (phenotypic) validity with the human disorder (with the caveats raised above). However, previous work has suggested that multiple fragile X symptoms can arise from the same core pathophysiology (Bear et al., 2004
; Bhakar et al., 2012
). The finding that lovastatin normalizes mGluR-LTD in the Fmr1
KO hippocampus to WT levels () is consistent with this idea. This result is intriguing, however, as protein synthesis inhibitors cannot correct the exaggerated mGluR-LTD in the Fmr1
KO (reviewed in (Bhakar et al., 2012
). The implication is that lovastatin is exerting additional beneficial effects on the Fmr1
KO beyond the reduction of protein synthesis. What these effects are remains to be determined, however it should be noted that the selective reduction of mGluR-LTD in the Fmr1
KO has been observed in a previous study using lithium (Choi et al., 2011
It will be of interest to assess in future studies the effect of lovastatin treatment on the full spectrum of fragile X phenotypes. Indeed, the findings that lovastatin can selectively quiet cortical hyperexcitability in the Fmr1
KO () as well as exaggerated LTD suggest it could potentially improve sensory and cognitive functions. Moreover, there is growing appreciation that disruptions in Ras signaling (Krab et al., 2008
) and synaptic protein synthesis (Kelleher and Bear, 2008
) may lie at the core of many autisms of unknown etiology, suggesting that lovastatin could have therapeutic utility in other ASDs as well as in other symptom domains.