The FMR1 gene, mutated in Fragile X syndrome patients, has been modeled in mice with a neomycin cassette inserted in exon 5 of the mouse Fmr1 gene creating an Fmr1 knockout (Fmr1 KO) allele. This results in animals lacking Fmr1 protein (Fmrp) expression in all tissues. We have created a new, more versatile Fmr1 in vivo KO model (Fmr1 KO2) and generated conditional Fmr1 KO (CKO) mice by flanking the promoter and first exon of Fmr1 with lox P sites. This enables us to create a null allele in specific cell types and at specific time points by crossing Fmr1 CKO mice with tissue specific or inducible cre-recombinase expressing mice. The new Fmr1 KO2 line does not express any Fmrp and also lacks detectable Fmr1 transcripts. Crossing the Fmr1 CKO line with a Purkinje cell-specific cre-recombinase expresser produces mice that are null for Fmr1 in Purkinje neurons but wild type in all other cell types.
"musculus ). Several mouse models have been generated, such as Fmr1 KO, Fmr1 conditional KO, Fmr1 conditional restoration (Bakker et al. 1994; Mientjes et al. 2006), and recently a mouse model for the I304N mutation, Fmr1 I304N (Zang et al. 2009). All these lines are available in different strains, such as A/J, C57Bl/6, 129/Ola, FVB, Balb, DBA, and many more (Paradee et al. 1999; Pietropaolo et al. 2011; Spencer et al. 2011). "
[Show abstract][Hide abstract] ABSTRACT: Fragile X syndrome (FXS) is considered the leading inherited cause of intellectual disability and autism. In FXS, the fragile X mental retardation 1 (FMR1) gene is silenced and the fragile X mental retardation protein (FMRP) is not expressed, resulting in the characteristic features of the syndrome. Despite recent advances in understanding the pathophysiology of FXS, there is still no cure for this condition; current treatment is symptomatic. Preclinical research is essential in the development of potential therapeutic agents.
This review provides an overview of the preclinical evidence supporting metabotropic glutamate receptor 5 (mGluR5) antagonists as therapeutic agents for FXS.
According to the mGluR theory of FXS, the absence of FMRP leads to enhanced glutamatergic signaling via mGluR5, which leads to increased protein synthesis and defects in synaptic plasticity including enhanced long-term depression. As such, efforts to develop agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. Animal models, particularly the Fmr1 knockout mouse model, have become invaluable in exploring therapeutic approaches on an electrophysiological, behavioral, biochemical, and neuroanatomical level. Two direct approaches are currently being investigated for FXS treatment: reactivating the FMR1 gene and compensating for the lack of FMRP. The latter approach has yielded promising results, with mGluR5 antagonists showing efficacy in clinical trials.
Targeting mGluR5 is a valid approach for the development of therapeutic agents that target the underlying pathophysiology of FXS. Several compounds are currently in development, with encouraging results.
"All behavioral procedures took place during the animal light cycle. Male fmr1−/− mice on a C57BL/6J genetic background  aged 10 to 11 weeks (P70 - 80) (fmr1−/− ) were used, with wild-type littermates used as control group. Mice were genotyped by tail PCR as described by . "
[Show abstract][Hide abstract] ABSTRACT: Fear behavior is vital for survival and involves learning contingent associations of non-threatening cues with aversive stimuli. In contrast, excessive levels of fear can be maladaptive and lead to anxiety disorders. Generally, extensive sessions of extinction training correlates with reduced spontaneous recovery. The molecular mechanisms underlying the long-term inhibition of fear recovery following repeated extinction training are not fully understood. Here we show that in rats, prolonged extinction training causes greater reduction in both fear-potentiated startle and spontaneous recovery. This effect was specifically blocked by metabotropic glutamate receptor 5 (mGluR5), but not by mGluR1 antagonists and by a protein synthesis inhibitor. Similar inhibition of memory recovery following prolonged extinction training was also observed in mice. In agreement with the instrumental role of mGluR5 in the prolonged inhibition of fear recovery, we found that FMR1-/- mice which exhibit enhanced mGluR5-mediated signaling exhibit lower spontaneous recovery of fear after extinction training than wild-type littermates. At the molecular level, we discovered that prolonged extinction training reversed the fear conditioning-induced increase in surface expression of GluR1, AMPA/NMDA ratio, postsynaptic density-95 (PSD-95) and synapse-associated protein-97 (SAP97). Accordingly, delivery of Tat-GluR23Y, a synthetic peptide that blocks AMPA receptor endocytosis, inhibited prolonged extinction training-induced inhibition of fear recovery. Together, our results demonstrate that prolonged extinction training results in the mGluR5-dependent long-term inhibition of fear recovery. This effect may involve the degradation of original memory and may explain the beneficial effects of prolonged exposure therapy for the treatment of phobias.
PLoS ONE 06/2013; 8(3):e59580. DOI:10.1371/journal.pone.0059580 · 3.23 Impact Factor
"Therefore , studies of early neural development and its correlation with FMR1 gradual inactivation may shed light on the pathophysiology of FXS and the etiology of intellectual disability. A number of FMR1 knock-out (KO) animal models have been generated (D'Hulst and Kooy, 2009; den Broeder et al., 2009; Lim et al., 2005; Mientjes et al., 2006; Wan et al., 2000), but they do not express FMR1 even at early stage of development (Chen et al., 2010). Human in-vitro models for studying FXS include post-mortem adult neurons (Irwin et al., 2001), adult neural progenitors (Schwartz et al., 2005), or fetal neural progenitor cells (Bhattacharyya et al., 2008; Castren et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: Background / Purpose:
The aim of this study was to investigate the mechanism(s) by which neural differentiation is impaired during embryonic development of FX affected fetuses and how the developmentally regulated silencing of FMR1 expression is related to mental retardation.
Neural differentiation induced FMR1 down regulation in FX-hESC, similar to the natural process. Abnormal neurogenesis & aberrant gene expression were found already at early stages of differentiation, leading to poor neuronal maturation. FX-neurons were electrophysiologically functional and contained the appropriate synaptic machinery but displayed poor spontaneous synaptic activity and no response to glutamate.
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