SummaryExcessive mRNA translation downstream of group I metabotropic glutamate receptors (mGlu1/5) is a core pathophysiology of fragile X syndrome (FX); however, the differentially translating mRNAs that contribute to altered neural function are not known. We used translating ribosome affinity purification (TRAP) and RNA-seq to identify mistranslating mRNAs in CA1 pyramidal neurons of the FX mouse model (Fmr1−/y) hippocampus, which exhibit exaggerated mGlu1/5-induced long-term synaptic depression (LTD). In these neurons, we find that the Chrm4 transcript encoding muscarinic acetylcholine receptor 4 (M4) is excessively translated, and synthesis of M4 downstream of mGlu5 activation is mimicked and occluded. Surprisingly, enhancement rather than inhibition of M4 activity normalizes core phenotypes in the Fmr1−/y, including excessive protein synthesis, exaggerated mGluR-LTD, and audiogenic seizures. These results suggest that not all excessively translated mRNAs in the Fmr1−/y brain are detrimental, and some may be candidates for enhancement to correct pathological changes in the FX brain.

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The cholesterol-lowering drug lovastatin corrects neurological phenotypes in animal models of fragile X syndrome (FX), a commonly identified genetic cause of autism and intellectual disability. The therapeutic efficacy of lovastatin is being tested in clinical trials for FX, however the structurally similar drug simvastatin has been proposed as an alternative due to an increased potency and brain penetrance. Here, we perform a side-by-side comparison of the effects of lovastatin and simvastatin treatment on two core phenotypes in the Fmr1 -/y mouse model. We find that while lovastatin normalizes excessive hippocampal protein synthesis and reduces audiogenic seizures (AGS) in the Fmr1 -/y mouse, simvastatin does not correct either phenotype. These results caution against the assumption that simvastatin is a valid alternative to lovastatin for the treatment of FX. Introduction:Fragile X syndrome (FX) is a monogenic neurodevelopmental disorder characterized by severe intellectual disability (ID), autism, hypersensitivity to sensory stimulation and epilepsy [1]. FX occurs in 1:4000 males and 1:8000 females, making it one of the most commonly identified genetic causes of autism and ID [1,2]. The FMR1 gene mutated in FX encodes Fragile X Mental Retardation Protein (FMRP), which represses mRNA translation in neurons [3,4]. Studies of the Fmr1 -/y mouse model of FX reveal that excessive cerebral protein synthesis is a major consequence of Fmr1 deletion [5-9], which can be normalized through antagonism of metabotropic glutamate receptor 5 (mGlu 5 ) or the downstream extracellular regulated kinase 1/2 (ERK1/2) MAP kinase signalling pathway [7,[10][11][12][13]. These strategies correct multiple neurological phenotypes in the Fmr1 -/y mouse, including an enhanced susceptibility to audiogenic seizures (AGS) [7,10,11,14]. The current challenge is to successfully transition these therapeutic approaches to the clinic.In previous work we showed that the statin drug lovastatin, currently used for the treatment of high cholesterol in adults and children, reduces ERK1/2 activation and resolves neuropathology in the Fmr1 -/y mouse model [15]. Lovastatin was the first statin drug developed and has been shown to be remarkably effective in lowering cholesterol with minimal side effects [16]. In FX, the therapeutic relevance of lovastatin is in the dampening of ERK1/2 signalling that occurs by reducing the activation of the upstream GTPase Ras [17,18]. By targeting the same mevalonate pathway that produces cholesterol, lovastatin limits the availability of farnesyl pyrophosphate precursor that is required for the membrane association and activation of Ras [17][18][19]. By this mechanism, lovastatin has been shown to successfully correct electrophysiological and behavioural phenotypes in the mouse model of Neurofibromatosis Type 1 (NF1), a neurodevelopmental disorder of excess Ras [20].In the Fmr1 -/y mouse, the reduction of Ras-ERK1/2 by lovastatin ameliorates hippocampal epileptogenesis and neocortical hyperexcitability and significantl...

The negative results of our study prompt to continue the search for potential disease modifiers in SBMA outside the AR gene.