Group I metabotropic glutamate receptor antagonists alter select behaviors in a mouse model for fragile X syndrome.
ABSTRACT Studies in the Fmr1 knockout (KO) mouse, a model of fragile X syndrome (FXS), suggest that excessive signaling through group I metabotropic glutamate receptors (mGluRs), comprised of subtypes mGluR1 and mGluR5, may play a role in the pathogenesis of FXS. Currently, no studies have assessed the effect of mGluR1 modulation on Fmr1 KO behavior, and there has not been an extensive behavioral analysis of mGluR5 manipulation in Fmr1 KO mice.
The goals for this study were to determine if pharmacologic blockade of mGluR1 may affect Fmr1 KO behavior as well as to expand on the current literature regarding pharmacologic blockade of mGluR5 on Fmr1 KO behavior.
Reduction of mGluR1 or mGluR5 activity was evaluated on a variety of behavioral assays in wild-type (WT) and Fmr1 KO mice through the use of antagonists: JNJ16259685 (JNJ, mGluR1 antagonist) and MPEP (mGluR5 antagonist).
JNJ and MPEP decreased marble burying in both WT and Fmr1 KO mice without reductions in activity. Neither JNJ nor MPEP affected the prepulse inhibition in either WT or Fmr1 KO mice. JNJ did not affect Fmr1 KO motor coordination but did impair WT performance. MPEP improved a measure of motor learning in Fmr1 KO but not WT mice. While both JNJ and MPEP decreased the audiogenic seizures in the Fmr1 KO, MPEP completely abolished the manifestation of seizures.
These data illustrate that, while the manipulation of either mGluR1 or mGluR5 can affect select behaviors in the Fmr1 KO, we observe greater effects upon mGluR5 reduction.
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ABSTRACT: Autism spectrum disorders (ASDs) are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases.Frontiers in Cellular Neuroscience 02/2015; 9:55. DOI:10.3389/fncel.2015.00055 · 4.18 Impact Factor
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ABSTRACT: Fragile X Syndrome (FXS) is a commonly inherited form of intellectual disability and one of the leading genetic causes for autism spectrum disorder. Clinical symptoms of FXS can include impaired cognition, anxiety, hyperactivity, social phobia, and repetitive behaviors. FXS is caused by a CGG repeat mutation which expands a region on the X chromosome containing the FMR1 gene. In FXS, a full mutation (> 200 repeats) leads to hypermethylation of FMR1, an epigenetic mechanism that effectively silences FMR1 gene expression and reduces levels of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that is important for the regulation of protein expression. In an effort to further understand how loss of FMR1 and FMRP contribute to FXS symptomology, several FXS animal models have been created. The most well characterized rodent model is the Fmr1 knockout (KO) mouse, which lacks FMRP protein due to a disruption in its Fmr1 gene. Here, we review the behavioral phenotyping of the Fmr1 KO mouse to date, and discuss the clinical relevance of this mouse model to the human FXS condition. While much remains to be learned about FXS, the Fmr1 KO mouse is a valuable tool for understanding the repercussions of functional loss of FMRP and assessing the efficacy of pharmacological compounds in ameliorating the molecular and behavioral phenotypes relevant to FXS.11/2014; 3(4):118-33. DOI:10.5582/irdr.2014.01024
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ABSTRACT: The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the FMR1 gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain and nonneuronal cells. During brain development, FMRP controls the expression of key molecules involved in receptor signaling, cytoskeleton remodeling, protein synthesis and, ultimately, spine morphology. Symptoms associated with FXS include neurodevelopmental delay, cognitive impairment, anxiety, hyperactivity, and autistic-like behavior. Twenty years ago the first Fmr1 KO mouse to study FXS was generated, and several years later other key models including the mutant Drosophila melanogaster, dFmr1, have further helped the understanding of the cellular and molecular causes behind this complex syndrome. Here, we review to which extent these biological models are affected by the absence of FMRP, pointing out the similarities with the observed human dysfunction. Additionally, we discuss several potential treatments under study in animal models that are able to partially revert some of the FXS abnormalities.Learning & memory (Cold Spring Harbor, N.Y.) 10/2014; 21(10):543-555. DOI:10.1101/lm.035956.114 · 4.38 Impact Factor