scholarly journals Altered Hippocampal Synaptic Plasticity in the Fmr1 Gene Family Knockout Mouse Models

2009 ◽  
Vol 101 (5) ◽  
pp. 2572-2580 ◽  
Author(s):  
Jing Zhang ◽  
Lingfei Hou ◽  
Eric Klann ◽  
David L. Nelson
Keyword(s):  
Protein Synthesis ◽  
Mental Retardation ◽  
Synaptic Plasticity ◽  
Knockout Mice ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Double Knockout ◽  
Fragile X Mental Retardation ◽  
Presynaptic Plasticity

Fragile X syndrome (FXS) is the most common form of inherited mental retardation. The syndrome results from the absence of the fragile X mental retardation protein (FMRP), which is encoded by the fragile X mental retardation 1 ( FMR1) gene. FMR1 and its two paralogs, fragile X–related genes 1 and 2 ( FXR1 and -2), form the Fmr1 gene family. Here, we examined long-lasting synaptic plasticity in Fmr1 knockout, Fxr2 knockout, and Fmr1/ Fxr2 double knockout mice. We found that metabotropic glutamate receptor–dependent long-term depression (mGluR-LTD) in the hippocampus was affected in Fmr1 knockout, Fxr2 knockout, and Fmr1/ Fxr2 double knockout mice at young ages (4–6 wk old). In addition, Fmr1/ Fxr2 double knockout mice showed significant deficiencies relative to either Fmr1 or Fxr2 knockout mice in baseline synaptic transmission and short-term presynaptic plasticity, suggesting FMRP and FXR2P may contribute in a cooperative manner to pathways regulating presynaptic plasticity. However, compared with wild-type littermates, late-phase long-term potentiation (L-LTP) was unaltered in all knockout mice at 4–6 mo of age. Interestingly, although Fmr1/ Fxr2 double knockout mice exhibited a more robust enhancement in mGluR-LTD compared with that in Fmr1 knockout mice, Fxr2 knockout mice exhibited reduced mGluR-LTD. Furthermore, unlike Fmr1 knockout mice, mGluR-LTD in Fxr2 knockout mice required new protein synthesis, whereas mGluR-LTD in Fmr1/ Fxr2 double knockout mice was partially dependent on protein synthesis. These results indicated that both FMRP and FXR2P function in synaptic plasticity and that they likely operate in related but independent pathways.

scholarly journals FMRP and CYFIP1 at the Synapse and Their Role in Psychiatric Vulnerability

2020 ◽  
Vol 6 (1-2) ◽  
pp. 5-19 ◽  
Author(s):  
Nicholas E. Clifton ◽  
Kerrie L. Thomas ◽  
Lawrence S. Wilkinson ◽  
Jeremy Hall ◽  
Simon Trent
Keyword(s):  
Mental Retardation ◽  
Synaptic Plasticity ◽  
Psychiatric Disorders ◽  
Fragile X ◽  
Synaptic Proteins ◽  
Interacting Protein ◽  
Fragile X Mental Retardation ◽  
Risk Variants ◽  
Mental Retardation Protein

There is increasing awareness of the role genetic risk variants have in mediating vulnerability to psychiatric disorders such as schizophrenia and autism. Many of these risk variants encode synaptic proteins, influencing biological pathways of the postsynaptic density and, ultimately, synaptic plasticity. Fragile-X mental retardation 1 (FMR1) and cytoplasmic fragile-X mental retardation protein (FMRP)-interacting protein 1 (CYFIP1) contain 2 such examples of highly penetrant risk variants and encode synaptic proteins with shared functional significance. In this review, we discuss the biological actions of FMRP and CYFIP1, including their regulation of (i) protein synthesis and specifically FMRP targets, (ii) dendritic and spine morphology, and (iii) forms of synaptic plasticity such as long-term depression. We draw upon a range of preclinical studies that have used genetic dosage models of FMR1 and CYFIP1 to determine their biological function. In parallel, we discuss how clinical studies of fragile X syndrome or 15q11.2 deletion patients have informed our understanding of FMRP and CYFIP1, and highlight the latest psychiatric genomic findings that continue to implicate FMRP and CYFIP1. Lastly, we assess the current limitations in our understanding of FMRP and CYFIP1 biology and how they must be addressed before mechanism-led therapeutic strategies can be developed for psychiatric disorders.

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 Short- and Long-Term Memory Are Modulated by Multiple Isoforms of the Fragile X Mental Retardation Protein

2010 ◽  
Vol 30 (19) ◽  
pp. 6782-6792 ◽  
Author(s):  
P. Banerjee ◽  
B. P. Schoenfeld ◽  
A. J. Bell ◽  
C. H. Choi ◽  
M. P. Bradley ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Fragile X ◽  
Long Term Memory ◽  
Term Memory ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Short And Long Term

Focal areas of a high rate of fragile X in Indonesia: a long term follow up

2019 ◽  
Vol 5 (2) ◽  
pp. 67-68
Author(s):  
Sultana MH Faradz ◽  
Tri Indah Winarni
Keyword(s):  
Mental Retardation ◽  
Behavioral Problems ◽  
Fragile X ◽  
Autism Spectrum ◽  
High Rate ◽  
Learning Ability ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats ◽  
Long Term Follow Up

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID) and a leading cause of autism spectrum disorder (ASD). FXS is caused by an expansion of CGG repeats >200 in the 5′ untranslated region of the promotor region fragile X mental retardation 1 gene (FMR1), which is located on Xq27.3.  The abnormal CGG expansion leads to methylation and transcriptional silencing of the FMR1 gene, resulting in a reduction or loss of fragile X mental retardation 1 protein (FMRP) and causes long, thin, and immature dendritic spines, which lead to deficits in cognitive function, behavioral problems, and learning ability

scholarly journals Alterations of Amino Acids and Monoamine Metabolism in Male Fmr1 Knockout Mice: A Putative Animal Model of the Human Fragile X Mental Retardation Syndrome

2001 ◽  
Vol 8 (4) ◽  
pp. 285-298 ◽  
Author(s):  
Michael Gruss ◽  
Katharina Braun
Keyword(s):  
Amino Acids ◽  
Animal Model ◽  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Knockout Mice ◽  
Fragile X ◽  
Fragile X Mental Retardation ◽  
Behavioral Abnormalities ◽  
Cortical Regions ◽  
Knockout Animals

The Fragile X syndrome, a common form of mental retardation in humans, is caused by silencing the fragile X mental retardation (FMR1) geneleading to the absence of the encoded fragile X mental retardation protein 1 (FMRP). We describe morphological and behavioral abnormalities for both affected humans and Fmr1 knockout mice, a putative animal model for the human Fragile X syndrome. The aim of the present study was to identify possible neurochemical abnormalities in Fmr1 knockout mice, with particular focus on neurotransmission. Significant region-specific differences: of basal neurotransmitter and metabolite levels were found between wildtype and Fmr1 knockout animals, predominantly in juveniles (post-natal days 28 to 31). Adults (postnatal days 209 to 221) showed only few abnormalities as compared with the wildtype. In juvenile knockout mice, aspartate and taurine were especially increased in cortical regions, striatum, hippocampus, cerebellum, and brainstem. In addition, juveniles showed an altered balance between excitatory and inhibitory amino acids in the caudal cortex, hippocampus, and brainstem. We detected very few differences in monoamine turnover in both age stages. The results presented here provide the first evidence that lack of FMRP expression in FMRP knockout mice is accompanied by age-dependent, region-specific alterations in neurotransmission.

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