Metabotropic Receptor-Dependent Long-Term Depression Persists in the Absence of Protein Synthesis in the Mouse Model of Fragile X Syndrome

2006 ◽  
Vol 95 (5) ◽  
pp. 3291-3295 ◽  
Author(s):  
Elena D. Nosyreva ◽  
Kimberly M. Huber
Keyword(s):  
Protein Synthesis ◽  
Mental Retardation ◽  
Mouse Model ◽  
Fragile X Syndrome ◽  
Rna Binding ◽  
Fragile X ◽  
Surface Expression ◽  
Long Term Depression ◽  
Fragile X Mental Retardation

Fragile X syndrome (FXS), a form of human mental retardation, is caused by loss of function mutations in the fragile X mental retardation gene ( FMR1). The protein product of FMR1, fragile X mental retardation protein (FMRP) is an RNA-binding protein and may function as a translational suppressor. Metabotropic glutamate receptor–dependent long-term depression (mGluR-LTD) in hippocampal area CA1 is a form of synaptic plasticity that relies on dendritic protein synthesis. mGluR-LTD is enhanced in the mouse model of FXS, Fmr1 knockout (KO) mice, suggesting that FMRP negatively regulates translation of proteins required for LTD. Here we examine the synaptic and cellular mechanisms of mGluR-LTD in KO mice and find that mGluR-LTD no longer requires new protein synthesis, in contrast to wild-type (WT) mice. We further show that mGluR-LTD in KO and WT mice is associated with decreases in AMPA receptor (AMPAR) surface expression, indicating a similar postsynaptic expression mechanism. However, like LTD, mGluR-induced decreases in AMPAR surface expression in KO mice persist in protein synthesis inhibitors. These results are consistent with recent findings of elevated protein synthesis rates and synaptic protein levels in Fmr1 KO mice and suggest that these elevated levels of synaptic proteins are available to increase the persistence of LTD without de novo protein synthesis.

scholarly journals Kinase pathway inhibition restores PSD95 induction in neurons lacking fragile X mental retardation protein

2019 ◽  
pp. 201812056
Author(s):  
Ying Yang ◽  
Yang Geng ◽  
Dongyun Jiang ◽  
Lin Ning ◽  
Hyung Joon Kim ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Mental Retardation ◽  
Rna Binding ◽  
Fragile X ◽  
Alternative Pathways ◽  
Fragile X Mental Retardation ◽  
Mrna Targets ◽  
Mental Retardation Protein ◽  
Pathway Inhibition

Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. FXS is caused by loss of expression of fragile X mental retardation protein (FMRP), an RNA-binding protein that regulates translation of numerous mRNA targets, some of which are present at synapses. While protein synthesis deficits have long been postulated as an etiology of FXS, how FMRP loss affects distributions of newly synthesized proteins is unknown. Here we investigated the role of FMRP in regulating expression of new copies of the synaptic protein PSD95 in an in vitro model of synaptic plasticity. We find that local BDNF application promotes persistent accumulation of new PSD95 at stimulated synapses and dendrites of cultured neurons, and that this accumulation is absent in FMRP-deficient mouse neurons. New PSD95 accumulation at sites of BDNF stimulation does not require known mechanisms regulating FMRP–mRNA interactions but instead requires the PI3K-mTORC1-S6K1 pathway. Surprisingly, in FMRP-deficient neurons, BDNF induction of new PSD95 accumulation can be restored by mTORC1-S6K1 blockade, suggesting that constitutively high mTORC1-S6K1 activity occludes PSD95 regulation by BDNF and that alternative pathways exist to mediate induction when mTORC1-S6K1 is inhibited. This study provides direct evidence for deficits in local protein synthesis and accumulation of newly synthesized protein in response to local stimulation in FXS, and supports mTORC1-S6K1 pathway inhibition as a potential therapeutic approach for FXS.

scholarly journals New Targeted Treatments for Fragile X Syndrome

2019 ◽  
Vol 15 (4) ◽  
pp. 251-258 ◽  
Author(s):  
Dragana Protic ◽  
Maria J. Salcedo-Arellano ◽  
Jeanne Barbara Dy ◽  
Laura A. Potter ◽  
Randi J. Hagerman
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Behavioral Problems ◽  
Rna Binding ◽  
Fragile X ◽  
Symptomatic Treatment ◽  
Fmr1 Gene ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5’ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.

scholarly journals Dynamic Translational and Proteasomal Regulation of Fragile X Mental Retardation Protein Controls mGluR-Dependent Long-Term Depression

Neuron ◽  
2006 ◽  
Vol 51 (4) ◽  
pp. 441-454 ◽  
Author(s):  
Lingfei Hou ◽  
Marcia D. Antion ◽  
Daoying Hu ◽  
Corinne M. Spencer ◽  
Richard Paylor ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X ◽  
Long Term Depression ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein

scholarly journals An “Omic” Overview of Fragile X Syndrome

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 433
Author(s):  
Olivier Dionne ◽  
François Corbin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Medical Problems ◽  
Biochemical Alterations ◽  
Fragile X Mental Retardation ◽  
Wide Range

Fragile X syndrome (FXS) is a neurodevelopmental disorder associated with a wide range of cognitive, behavioral and medical problems. It arises from the silencing of the fragile X mental retardation 1 (FMR1) gene and, consequently, in the absence of its encoded protein, FMRP (fragile X mental retardation protein). FMRP is a ubiquitously expressed and multifunctional RNA-binding protein, primarily considered as a translational regulator. Pre-clinical studies of the past two decades have therefore focused on this function to relate FMRP’s absence to the molecular mechanisms underlying FXS physiopathology. Based on these data, successful pharmacological strategies were developed to rescue fragile X phenotype in animal models. Unfortunately, these results did not translate into humans as clinical trials using same therapeutic approaches did not reach the expected outcomes. These failures highlight the need to put into perspective the different functions of FMRP in order to get a more comprehensive understanding of FXS pathophysiology. This work presents a review of FMRP’s involvement on noteworthy molecular mechanisms that may ultimately contribute to various biochemical alterations composing the fragile X phenotype.

scholarly journals Selective role of the translin/trax RNase complex in hippocampal synaptic plasticity

2020 ◽  
Author(s):  
Alan Jung Park ◽  
Mahesh Shivarama Shetty ◽  
Jay M. Baraban ◽  
Ted Abel
Keyword(s):  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Mouse Model ◽  
Fragile X Syndrome ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Local Protein Synthesis ◽  
Hippocampal Synaptic Plasticity ◽  
Local Protein

Abstract Activity-dependent local protein synthesis is critical for synapse-specific, persistent plasticity. Abnormalities in local protein synthesis have been implicated in psychiatric disorders. We have recently identified the translin/trax microRNA-degrading enzyme as a novel mediator of protein synthesis at activated synapses. Additionally, mice lacking translin/trax exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome. Therefore, identifying signaling pathways interacting with translin/trax to support persistent synaptic plasticity is a translationally relevant goal. Here, as a first step to achieve this goal, we have assessed the requirement of translin/trax for multiple hippocampal synaptic plasticity paradigms that rely on distinct molecular mechanisms. We found that mice lacking translin/trax exhibited selective impairment in a form of persistent hippocampal plasticity, which requires postsynaptic PKA activity. In contrast, enduring forms of plasticity that are dependent on presynaptic PKA were unaffected. Furthermore, these mice did not display exaggerated metabotropic glutamate receptor-mediated long-term synaptic depression, a hallmark of the mouse model of fragile X syndrome. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling.

scholarly journals Homeostatic Inhibitory Control of Cortical Hyperexcitability in Fragile X Syndrome

2018 ◽  
Author(s):  
C.A. Cea-Del Rio ◽  
A. Nunez-Parra ◽  
S. Freedman ◽  
D. Restrepo ◽  
M.M. Huntsman
Keyword(s):  
Synaptic Plasticity ◽  
Mouse Model ◽  
Somatosensory Cortex ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Synaptic Function ◽  
Network Activity ◽  
Inhibitory Input ◽  
Long Term Depression

AbstractIn mouse models of Fragile X Syndrome (FXS), cellular and circuit hyperexcitability are a consequence of altered brain development [reviewed in (Contractor et al., 2015)]. Mechanisms that favor or hinder plasticity of synapses could affect neuronal excitability. This includes inhibitory long term depression (I-LTD) – a heterosynaptic form of plasticity that requires the activation of metabotropic glutamate receptors (mGluRs). Differential circuit maturation leads to shifted time points for critical periods of synaptic plasticity across multiple brain regions (Harlow et al., 2010; He et al., 2014), and disruptions of the development of excitatory and inhibitory synaptic function are also observed both during development and into adulthood (Vislay et al., 2013). However, little is known about how this hyperexcitable environment affects inhibitory synaptic plasticity. Our results demonstrate that the somatosensory cortex of the Fmr1 KO mouse model of FXS exhibits increased GABAergic spontaneous activity, a faulty mGluR-mediated inhibitory input and impaired plasticity processes. We find the overall diminished mGluR activation in the Fmr1 KO mice leads to both a decreased spontaneous inhibitory postsynaptic input to principal cells and also to a disrupted form of inhibitory long term depression (I-LTD). In cortical synapses, this I-LTD is dependent on mGluR activation and the mobilization endocannabinoids (eCBs). Notably, these data suggest enhanced hyperexcitable phenotypes in FXS may be homeostatically counterbalanced by the inhibitory drive of the network and its altered response to mGluR modulation.Significance StatementFragile X Syndrome is a pervasive neurodevelopmental disorder characterized by intellectual disability, autism, epilepsy, anxiety and altered sensory sensitivity. In both in vitro and in vivo recordings in the somatosensory cortex of the Fmr1 knockout mouse model of Fragile X Syndrome we show that hyperexcitable network activity contributes to ineffective synaptic plasticity at inhibitory synapses. This increased excitability prevents cortical circuits from adapting to sensory information via ineffective plasticity mechanisms.

scholarly journals Selective role of the translin/trax RNase complex in hippocampal synaptic plasticity

2020 ◽  
Author(s):  
Alan Jung Park ◽  
Mahesh Shivarama Shetty ◽  
Jay M. Baraban ◽  
Ted Abel
Keyword(s):  
Protein Synthesis ◽  
Synaptic Plasticity ◽  
Mouse Model ◽  
Fragile X Syndrome ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Local Protein Synthesis ◽  
Hippocampal Synaptic Plasticity ◽  
Local Protein

AbstractActivity-dependent local protein synthesis is critical for synapse-specific, persistent plasticity. Abnormalities in local protein synthesis have been implicated in psychiatric disorders. We have recently identified the translin/trax microRNA-degrading enzyme as a novel mediator of protein synthesis at activated synapses. Additionally, mice lacking translin/trax exhibit some of the behavioral abnormalities found in a mouse model of fragile X syndrome. Therefore, identifying signaling pathways interacting with translin/trax to support persistent synaptic plasticity is a translationally relevant goal. Here, as a first step to achieve this goal, we have assessed the requirement of translin/trax for multiple hippocampal synaptic plasticity paradigms that rely on distinct molecular mechanisms. We found that mice lacking translin/trax exhibited selective impairment in a form of persistent hippocampal plasticity, which requires postsynaptic PKA activity. In contrast, enduring forms of plasticity that are dependent on presynaptic PKA were unaffected. Furthermore, these mice did not display exaggerated metabotropic glutamate receptor-mediated long-term synaptic depression, a hallmark of the mouse model of fragile X syndrome. Taken together, these findings demonstrate that translin/trax mediates long-term synaptic plasticity that is dependent on postsynaptic PKA signaling.

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