Carbamazepine restores neuronal signaling, protein synthesis and cognitive function in a mouse model of fragile X syndrome

ABSTRACTFragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, it is widely accepted that the lack of FMRP causes elevated protein synthesis and deregulation of neuronal signaling. Abnormal enhancement of the ERK½ (extracellular signal-regulated kinase ½) and PI3K-Akt (Phosphoinositide 3 kinase-protein kinase B) signaling pathways has been identified in both FXS patients and FXS mouse models. In this study, we show that carbamazepine, which is an FDA-approved drug and has been mainly used to treat seizure and neuropathic pain, corrects cognitive deficits including passive avoidance and object location memory in FXS mice. Carbamazepine also rescues hyper locomotion and social deficits. At the cellular level, carbamazepine dampens the elevated level of ERK½ and Akt signaling as well as protein synthesis in FXS mouse neurons. Together, these results advocate repurposing carbamazepine for FXS treatment.

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Carbamazepine Restores Neuronal Signaling, Protein Synthesis, and Cognitive Function in a Mouse Model of Fragile X Syndrome

International Journal of Molecular Sciences ◽

10.3390/ijms21239327 ◽

2020 ◽

Vol 21 (23) ◽

pp. 9327

Author(s):

Qi Ding ◽

Fan Zhang ◽

Yue Feng ◽

Hongbing Wang

Keyword(s):

Protein Synthesis ◽

Fragile X Syndrome ◽

Fragile X ◽

Genetic Disorder ◽

Cellular Level ◽

Neuronal Signaling ◽

Object Location Memory ◽

Extracellular Signal ◽

Elevated Protein ◽

Phosphoinositide 3 Kinase

Fragile X syndrome (FXS) is a leading genetic disorder of intellectual disability caused by the loss of the functional fragile X mental retardation protein (FMRP). To date, there is no efficacious mechanism-based medication for FXS. With regard to potential disease mechanisms in FXS, it is widely accepted that the lack of FMRP causes elevated protein synthesis and deregulation of neuronal signaling. Abnormal enhancement of the ERK½ (extracellular signal-regulated kinase ½) and PI3K-Akt (Phosphoinositide 3 kinase-protein kinase B) signaling pathways has been identified in both FXS patients and FXS mouse models. In this study, we show that carbamazepine, which is an FDA-approved drug and has been mainly used to treat seizure and neuropathic pain, corrects cognitive deficits including passive avoidance and object location memory in FXS mice. Carbamazepine also rescues hyper locomotion and social deficits. At the cellular level, carbamazepine dampens the elevated level of ERK½ and Akt signaling as well as protein synthesis in FXS mouse neurons. Together, these results advocate repurposing carbamazepine for FXS treatment.

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R-Baclofen Reverses a Social Behavior Deficit and Elevated Protein Synthesis in a Mouse Model of Fragile X Syndrome

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyv034 ◽

2015 ◽

Vol 18 (9) ◽

pp. pyv034 ◽

Cited By ~ 26

Author(s):

Mei Qin ◽

Tianjian Huang ◽

Michael Kader ◽

Leland Krych ◽

Zengyan Xia ◽

...

Keyword(s):

Protein Synthesis ◽

Social Behavior ◽

Mouse Model ◽

Fragile X Syndrome ◽

Fragile X ◽

Elevated Protein

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Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice

10.1101/2020.04.26.062281 ◽

2020 ◽

Author(s):

Sameer Aryal ◽

Francesco Longo ◽

Eric Klann

Keyword(s):

Protein Synthesis ◽

Fragile X Syndrome ◽

Fragile X ◽

Mrna Translation ◽

Ribosome Profiling ◽

Sequence Length ◽

Rna Seq ◽

Double Knockout ◽

Coding Sequence ◽

Mental Retardation Protein

AbstractLoss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP is widely thought to repress protein synthesis, but its translational targets and modes of control remain in dispute. We previously showed that genetic removal of p70 S6 kinase 1 (S6K1) corrects altered protein synthesis as well as synaptic and behavioral phenotypes in FXS mice. In this study, we examined the gene-specificity of altered mRNA translation in FXS and the mechanism of rescue with genetic reduction of S6K1 by carrying out ribosome profiling and RNA-Seq on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice. We observed reduced ribosome footprint abundance in the majority of differentially translated genes in the cortices of FXS mice. We used molecular assays to discover evidence that the reduction in ribosome footprint abundance reflects an increased rate of ribosome translocation, which is captured as a decrease in the number of translating ribosomes at steady state, and is normalized by inhibition of S6K1. We also found that genetic removal of S6K1 prevented a positive-to-negative gradation of alterations in translation efficiencies (RF/mRNA) with coding sequence length across mRNAs in FXS mouse cortices. Our findings reveal the identities of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS.

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Fmr1KO Mice as a Possible Model of Autistic Features

The Scientific World JOURNAL ◽

10.1100/tsw.2006.220 ◽

2006 ◽

Vol 6 ◽

pp. 1164-1176 ◽

Cited By ~ 90

Author(s):

Maude Bernardet ◽

Wim E. Crusio

Keyword(s):

Social Interactions ◽

Fragile X Syndrome ◽

Developmental Disorders ◽

Developmental Disorder ◽

Fragile X ◽

Cellular Level ◽

Restricted Interests ◽

Autism Research ◽

Hereditary Component ◽

Autistic Symptoms

Autism is a pervasive developmental disorder appearing before the age of 3, where communication and social interactions are impaired. It also entails stereotypic behavior or restricted interests. Although this disorder was first described in 1943, little is still known about its etiology and that of related developmental disorders. Work with human patients has provided many data on neuropathological and cognitive symptoms, but our understanding of the functional defects at the cellular level and how they come about remains sketchy. To improve this situation, autism research is in need of valid animal models. However, despite a strong hereditary component, attempts to identify genes have generally failed, suggesting that many different genes are involved. As a high proportion of patients suffering from the Fragile X Syndrome show many autistic symptoms, a mouse model of this disorder could potentially also serve as a model for autism. TheFmr1KO mouse is a valid model of the Fragile X Syndrome and many data on behavioral and sensory-motor characteristics of this model have been gathered. We present here an assessment of autistic features in this candidate model. We conclude thatFmr1KO mice display several autistic-like features, but more work is needed to validate this model.

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Hypersensitivity to mGluR5 and ERK1/2 Leads to Excessive Protein Synthesis in the Hippocampus of a Mouse Model of Fragile X Syndrome

Journal of Neuroscience ◽

10.1523/jneurosci.3888-10.2010 ◽

2010 ◽

Vol 30 (46) ◽

pp. 15616-15627 ◽

Cited By ~ 232

Author(s):

E. K. Osterweil ◽

D. D. Krueger ◽

K. Reinhold ◽

M. F. Bear

Keyword(s):

Protein Synthesis ◽

Mouse Model ◽

Fragile X Syndrome ◽

Fragile X

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Effects of chronic inhibition of phosphodiesterase-4D on behavior and regional rates of cerebral protein synthesis in a mouse model of fragile X syndrome

Neurobiology of Disease ◽

10.1016/j.nbd.2021.105485 ◽

2021 ◽

pp. 105485

Author(s):

Michael Rosenheck ◽

Carrie Sheeler ◽

Rachel Michelle Saré ◽

Mark E. Gurney ◽

Carolyn Beebe Smith

Keyword(s):

Protein Synthesis ◽

Mouse Model ◽

Fragile X Syndrome ◽

Fragile X ◽

Phosphodiesterase 4D ◽

Cerebral Protein Synthesis

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Isoform-selective phosphoinositide 3-kinase inhibition ameliorates a broad range of fragile X syndrome-associated deficits in a mouse model

Neuropsychopharmacology ◽

10.1038/s41386-018-0150-5 ◽

2018 ◽

Vol 44 (2) ◽

pp. 324-333 ◽

Cited By ~ 10

Author(s):

Christina Gross ◽

Anwesha Banerjee ◽

Durgesh Tiwari ◽

Francesco Longo ◽

Angela R. White ◽

...

Keyword(s):

Mouse Model ◽

Fragile X Syndrome ◽

Fragile X ◽

Kinase Inhibition ◽

Phosphoinositide 3 Kinase

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Computational analysis of transcriptome signature repurposes low dose trifluoperazine for the treatment of fragile X syndrome in mouse model

10.1101/683169 ◽

2019 ◽

Author(s):

Qi Ding ◽

Ferzin Sethna ◽

Xue-Ting Wu ◽

Zhuang Miao ◽

Ping Chen ◽

...

Keyword(s):

Fragile X Syndrome ◽

Computational Analysis ◽

Low Dose ◽

Fragile X ◽

Genetic Disorder ◽

Gene Signature ◽

Signature Database ◽

Therapeutic Value ◽

Elevated Activity ◽

Potential Therapeutic Intervention

ABSTRACTFragile X syndrome (FXS), caused by mutations in fragile X mental retardation 1 gene (FMR1), is a prevailing genetic disorder of intellectual disability and autism. Currently, there is no efficacious medication for FXS. Here, we use transcriptome landscape as a holistic molecular phenotype/endpoint to identify potential therapeutic intervention. Through in silico screening with public gene signature database, computational analysis of transcriptome profile in Fmr1 knockout (KO) neurons predicts therapeutic value of an FDA-approved drug trifluoperazine. Through experimental validation, we find that systemic administration of low dose trifluoperazine at 0.05 mg/kg attenuates multiple FXS- and autism-related behavioral symptoms. Moreover, computational analysis of transcriptome alteration caused by trifluoperazine suggests a new mechanism of action against PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) activity. Consistently, trifluoperazine suppresses PI3K activity and its down-stream targets Akt (protein kinase B) and S6K1 (S6 kinase 1) in neurons. Further, trifluoperazine normalizes the aberrantly elevated activity of Akt and S6K1 and enhanced protein synthesis in FXS mouse. In conclusion, our data demonstrate promising value of gene signature-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders, and suggest trifluoperazine as a potential practical treatment for FXS.

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