Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome

Suvrathan, Aparna; Hoeffer, Charles A.; Wong, Helen; Klann, Eric; Chattarji, Sumantra

doi:10.1073/pnas.1002262107

Cited by 125 publications

(117 citation statements)

References 41 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…Moreover, Harlow et al (2010) demonstrated impaired synaptic plasticity in the barrel cortex in Fmr1 KO mice during the critical period, a process that was shown to involve FMRP and mGlu 1/5 activity (Todd et al, 2003). Another study reported aberrant mGlu 1/5 -dependent neuronal plasticity in the amygdala of Fmr1 KO mice (Suvrathan et al, 2010). Furthermore, a specific, mGlu 1/5 -and protein synthesis-dependent form of hippocampal LTP was shown to be dysregulated in Fmr1 KO mice (Shang et al, 2009), and a recent study demonstrated that mGlu 1/5 -mediated priming of hippocampal LTP is, in contrast to wild-type, protein synthesisindependent in Fmr1 KO mice (Auerbach and Bear, 2010).…”

Section: Other Mglu 1/5 -Dependent Mechanisms In Fxsmentioning

confidence: 96%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

View full text Add to dashboard Cite

Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

show abstract

Section: Other Mglu 1/5 -Dependent Mechanisms In Fxsmentioning

confidence: 96%

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…For a more extensive review of Fmr1 knockout mice behavioral phenotypes see [180]. Behavior: social dominance [119]; sociability [132] Cognition: object recognition (chronic, not acute) [121]; fear conditioning [120]; associative motor learning (acute) [133]; inhibitory avoidance (chronic and acute) [129,133]; extinction memory (chronic) [129] LTP deficits in the amygdala and hippocampus (bath application) [128,134]; LTD (bath application) [135] startle response, † rotarod performance [131]; object recognition (acute) [121,134]; coordinate and categorical tasks (acute) [134]; analgesic response [121] mGlu5 NAMs used:…”

Section: Macro-orchidismmentioning

confidence: 99%

“…• MPEP [43,62,63,97,123,126,128,130,131,134] • MTEP [121] • Fenobam [124,126,133] • AFQ056 [119,125,127,132] CTEP [120,129] mGlu1 Genetic (het) Hyperexcitability: locomotor activity [118] Macro-orchidism, PPI, startle response, AGS, social interaction [118] Pharm Hyperexcitability: AGS (partially) [131] Startle response, rotarod [131] Muscarinic R (subtypes M1 and M4) Genetic (het) Plasticity and hyperexcitability: analgesic response, startle response (M4) [136] PPI, MB, light-dark transition (anxiety), AGS, macro-orchidism [136] Pharm Plasticity and hyperexcitability: AGS (M1+M4) [137,138] Cognition: passive avoidance (M4) [138] Passive avoidance (M1) [137] Group II mGlu N/A GSK3β antagonists used:…”

Section: Macro-orchidismmentioning

confidence: 99%

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

et al. 2015

View full text Add to dashboard Cite

Fragile X syndrome (FXS), an inherited intellectual disability often associated with autism, is caused by the loss of expression of the fragile X mental retardation protein. Tremendous progress in basic, preclinical, and translational clinical research has elucidated a variety of molecular-, cellular-, and system-level defects in FXS. This has led to the development of several promising therapeutic strategies, some of which have been tested in larger-scale controlled clinical trials. Here, we will summarize recent advances in understanding molecular functions of fragile X mental retardation protein beyond the well-known role as an mRNAbinding protein, and will describe current developments and emerging limitations in the use of the FXS mouse model as a preclinical tool to identify therapeutic targets. We will review the results of recent clinical trials conducted in FXS that were based on some of the preclinical findings, and discuss how the observed outcomes and obstacles will inform future therapy development in FXS and other autism spectrum disorders.Key Words Fragile X syndrome . FMRP . mRNA translation . clinical trials . biomarkers . language development Fragile X syndrome (FXS) is one of the first single gene disorders manifesting features of autism spectrum disorder (ASD) in which extensive study of the neurobiology and synaptic mechanisms of disease in cellular and animal models has been possible. The enormous progress in basic and preclinical and clinical translational work in FXS in the last several decades has allowed FXS to emerge as an important model to illustrate successes and hurdles in the development of future targeted treatments for autism and related developmental disorders. FXS is the most common known genetic cause of intellectual disability and ASD, with an estimated frequency of about 1 in 4000-5000 [1]. The disorder affects all ethnic groups worldwide. Genetics and Phenotype of FXSFXS is one of the fragile X-associated disorders (FXDs), all of which arise from a trinucleotide repeat (CGG) expansion mutation in the promoter region of FMR1. The CGG sequence is transcribed into the 5' untranslated region of FMR1 mRNA and thus length of the repeat sequence does not affect the sequence of the protein product of FMR1 [fragile X mental retardation protein (FMRP)] [2]. Small expansions in the gene (55-200 CGG repeats), termed the Bpremutation^, occur in about 1 in 430-468 males and 1 in 151-209 females in the USA [3,4], and is associated with risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency. Although the premutation is transcribed and translated to give FMRP, toxicity in fragile X-associated tremor/ataxia

show abstract

“…Loss of FMRP has been linked to various forms of long-term synaptic plasticity defects that depend on local protein synthesis in the postsynaptic neuron (3). In addition to disrupted metabotropic glutamate receptor signaling, which has been shown across multiple brain regions (4)(5)(6)(7), FMRP is necessary for activitydependent protein synthesis downstream of other signaling receptor pathways, including ACh, dopamine, and TrkB (8)(9)(10).…”

mentioning

confidence: 99%

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Myrick¹,

Deng²,

Hashimoto³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

132

View full text Add to dashboard Cite

Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre-and postsynaptic defects, yet whether the pre-and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP's canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP's interaction with the large-conductance calciumactivated potassium (BK) channels that modulate AP width. These results reveal a presynaptic-and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes.F ragile X syndrome (FXS) is the most common single-gene disorder responsible for intellectual disability (ID) in patients (1). Along with cognitive dysfunction, the syndrome typically presents with several other comorbidities, including behavioral and social impairments (anxiety and autism spectrum disorder), neurological defects (seizures and abnormal sleep patterns), and morphological abnormalities (dysmorphic facies and macroorchidism). Most patients inherit the syndrome through a maternal repeat expansion mutation that transcriptionally silences the FMR1 gene and results in loss of the gene product, FMRP.FMRP has complex multifaceted functions at synapses both in pre-and postsynaptic compartments. As an RNA binding protein, FMRP is best known for its function as a translation regulator in dendrites (2). Loss of FMRP has been linked to various forms of long-term synaptic plasticity defects that depend on local protein synthesis in the postsynaptic neuron (3). In addition to disrupted metabotropic glutamate receptor signaling, which has been shown across multiple brain regions (4-7), FMRP is necessary for activitydependent protein synthesis downstream of other signaling receptor pathways, including ACh, dopamine, and TrkB (8-10).Although postsynaptic control of translation is believed to be the dominant function of FMRP, it is unable to explain all of the pathophysiology observed in FXS animal models. For instance, in Drosophila, presynaptic expression of the FMR1 homolog, dfmr1, completely rescues the synaptic overgrowth phenotype at the neuromuscular junction (NMJ) in dfmr1-null mutants (11-13). In rodent brain, FMRP has been found in structures called fragile-X granules, which are ...

show abstract

Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome

Cited by 125 publications

References 41 publications

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

Contact Info

Product

Resources

About