Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missense Fmr1 mutant mouse model of Fragile X syndrome

AbstractFragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. FXS is usually caused by a CGG-repeat expansion in the FMR1 gene leading to its silencing and the loss-of-expression of the Fragile X Mental Retardation Protein (FMRP). Missense mutations were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS in these patients, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that the Fmr1R138Q hippocampus has an increased spine density associated with postsynaptic ultrastructural defects and increased AMPA receptor surface expression. Combining biochemical assays, high-resolution imaging and electrophysiological recordings, we also show that the mutation impairs the hippocampal long-term potentiation (LTP) and leads to socio-cognitive deficits in Fmr1R138Q mice. These findings reveal that the R138Q mutation impacts the synaptic functions of FMRP and highlight potential mechanisms causing FXS in FMRP-R138Q patients.

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Missense mutation of Fmr1 results in impaired AMPAR-mediated plasticity and socio-cognitive deficits in mice

Nature Communications ◽

10.1038/s41467-021-21820-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Marta Prieto ◽

Alessandra Folci ◽

Gwénola Poupon ◽

Sara Schiavi ◽

Valeria Buzzelli ◽

...

Keyword(s):

Mouse Model ◽

Cognitive Deficits ◽

Fragile X ◽

Long Term Potentiation ◽

Surface Expression ◽

Missense Mutations ◽

Spine Density ◽

Cgg Repeat ◽

Electrophysiological Recordings ◽

Receptor Surface Expression

AbstractFragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. CGG-repeat expansion in the FMR1 gene leads to FMR1 silencing, loss-of-expression of the Fragile X Mental Retardation Protein (FMRP), and is a common cause of FXS. Missense mutations in the FMR1 gene were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS caused by this mutation, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that, in the hippocampus of the Fmr1R138Q mice, neurons show an increased spine density associated with synaptic ultrastructural defects and increased AMPA receptor-surface expression. Combining biochemical assays, high-resolution imaging, electrophysiological recordings, and behavioural testing, we also show that the R138Q mutation results in impaired hippocampal long-term potentiation and socio-cognitive deficits in mice. These findings reveal the functional impact of the FMRP-R138Q mutation in a mouse model of FXS.

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Deficits in Trace Fear Memory and Long-Term Potentiation in a Mouse Model for Fragile X Syndrome

Journal of Neuroscience ◽

10.1523/jneurosci.1520-05.2005 ◽

2005 ◽

Vol 25 (32) ◽

pp. 7385-7392 ◽

Cited By ~ 188

Author(s):

M.-G. Zhao

Keyword(s):

Mouse Model ◽

Fragile X Syndrome ◽

Fragile X ◽

Long Term Potentiation ◽

Fear Memory ◽

Term Potentiation ◽

Trace Fear

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Decreased surface expression of the δ subunit of the GABA A receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome

Experimental Neurology ◽

10.1016/j.expneurol.2017.08.008 ◽

2017 ◽

Vol 297 ◽

pp. 168-178 ◽

Cited By ~ 12

Author(s):

Nianhui Zhang ◽

Zechun Peng ◽

Xiaoping Tong ◽

A. Kerstin Lindemeyer ◽

Yliana Cetina ◽

...

Keyword(s):

Mouse Model ◽

Fragile X Syndrome ◽

Granule Cells ◽

Fragile X ◽

Surface Expression ◽

Tonic Inhibition ◽

Gaba A ◽

Dentate Granule Cells

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Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of theFmr1Knockout Mouse Model of Fragile X Syndrome

Cerebral Cortex ◽

10.1093/cercor/bhv031 ◽

2015 ◽

Vol 26 (5) ◽

pp. 2084-2092 ◽

Cited By ~ 28

Author(s):

Henry G. S. Martin ◽

Olivier Lassalle ◽

Jonathan T. Brown ◽

Olivier J. Manzoni

Keyword(s):

Prefrontal Cortex ◽

Mouse Model ◽

Fragile X Syndrome ◽

Fragile X ◽

Long Term Potentiation ◽

Term Potentiation ◽

Age Dependent

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

Journal of Neurophysiology ◽

10.1152/jn.01316.2005 ◽

2006 ◽

Vol 95 (5) ◽

pp. 3291-3295 ◽

Cited By ~ 165

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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