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 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

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.

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