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Altered Hippocampal Synaptic Plasticity in the Fmr1 Gene Family Knockout Mouse Models
Open accessAbstract
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.
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“The fmr1 KO spares L-LTP (Zhang et al., 2009), while LTD is famously enhanced (Huber et al., 2002) (Fig. 5B1).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Zhang et al., 2009
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Metadata
- Authors
- Zhang, J., Hou, L., Klann, E., & Nelson, D. L.
- Affiliations
- Baylor College of Medicine (US)
- New York University (US)
- Venue
- Journal of Neurophysiology
- Publisher
- American Physiological Society
- Published
- 2009-05
- Volume
- 101
- Issue
- 5
- Pages
- 2572-2580
- ISSN
- 0022-3077 (ISSN-L)
- 1522-1598
- PMC
- PMC2681424
- OpenAlex
- W2009954395
- Cited by
- 126
- References
- 48
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 10 · 2023: 3 · 2021: 4 · 2020: 6 · 2019: 4 · 2018: 10 · 2017: 8 · 2016: 10 · 2015: 9 · 2014: 12 · 2013: 6 · 2012: 8
- FWCI
- 6.63
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurophysiology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS-047384, R01NS047384)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD 24064, HD-38038, P30HD024064, R01HD038038)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- fragile X syndrome, FMRP, FXR2, synaptic plasticity, long-term potentiation, presynaptic plasticity, synaptic transmission, protein synthesis dependence, hippocampus, intellectual disability
- MeSH terms
- Analysis of Variance, Animals, Anisomycin, Biophysics, Electric Stimulation, Female, Hippocampus, Male, Methoxyhydroxyphenylglycol, Mice, Inbred C57BL, Neural Pathways, Protein Synthesis Inhibitors, Synapses, RNA-Binding Proteins, Long-Term Potentiation, Receptors, Metabotropic Glutamate, Mice, Knockout, Patch-Clamp Techniques, Excitatory Postsynaptic Potentials, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, In Vitro Techniques
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