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Cited by 97Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchGenomic variations and chromosomal abnormalities

Haploinsufficiency of Cyfip1 Produces Fragile X-Like Phenotypes in Mice

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Bozdagi, Ozlem, Sakurai, Takeshi, Dorr, Nathan, Pilorge, Marion, Takahashi, Nagahide, Buxbaum, Joseph D.·2012·PLoS ONE
DOI 10.1371/journal.pone.0042422PMC PMC3416859
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Abstract

BACKGROUND: Copy number variation (CNV) at the 15q11.2 region, which includes a gene that codes for CYFIP1 (cytoplasmic FMR1 interacting protein 1), has been implicated in autism, intellectual disability and additional neuropsychiatric phenotypes. In the current study we studied the function of Cyfip1 in synaptic physiology and behavior, using mice with a disruption of the Cyfip1 gene. METHODOLOGY/PRINCIPAL FINDINGS: We observed that in Cyfip1 heterozygous mice metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD) induced by paired-pulse low frequency stimulation (PP-LFS) was significantly increased in comparison to wildtype mice. In addition, mGluR-LTD was not affected in the presence of protein synthesis inhibitor in the Cyfip1 heterozygous mice, while the same treatment inhibited LTD in wildtype littermate controls. mGluR-agonist (RS)-3,5-dihydroxyphenylglycine (DHPG)-induced LTD was also significantly increased in hippocampal slices from Cyfip1 heterozygous mice and again showed independence from protein synthesis only in the heterozygous animals. Furthermore, we observed that the mammalian Target of Rapamycin (mTOR) inhibitor rapamycin was only effective at reducing mGluR-LTD in wildtype animals. Behaviorally, Cyfip1 heterozygous mice showed enhanced extinction of inhibitory avoidance. Application of both mGluR5 and mGluR1 antagonist to slices from Cyfip1 heterozygous mice reversed the increase in DHPG-induced LTD in these mice. CONCLUSIONS/SIGNIFICANCE: These results demonstrate that haploinsufficiency of Cyfip1 mimics key aspects of the phenotype of Fmr1 knockout mice and are consistent with the hypothesis that these effects are mediated by interaction of Cyfip1 and Fmrp in regulating activity-dependent translation. The data provide support for a model where CYFIP1 haploinsufficiency in patients results in intermediate phenotypes increasing risk for neuropsychiatric disorders.

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  • How both deletions and duplications affecting Cyfip1 expression produce similar neuropsychiatric phenotypes has not yet been addressed.

    “Furthermore, how both deletions and duplications affecting Cyfip1 expression produce similar neuropsychiatric phenotypes has also not yet been addressed.34,35”

    From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [35]

    The Discussion (page not provided) cites evidence linking both 15q11.2 deletions and duplications to psychiatric phenotypes, but its functional analysis examines reduced Cyfip1 expression in heterozygous mice. It does not state that the mechanism by which both changes produce similar phenotypes had not yet been addressed. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Cyfip1 KO animals are embryonic-lethal.

    “Because Cyfip1 KO animals are embryonic-lethal (our observation and Bozdagi et al., 2012)”

    From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Bozdagi et al., 2012

  • Effects of CYFIP1 reduction on dendritic spines are compatible with the enhanced mGluR-dependent LTD and behavioral abnormalities caused by Cyfip1 haploinsufficiency, similar to the phenotype observed in Fmr1 KO mice.

    “Effects of CYFIP1 reduction on dendritic spines are compatible with the enhanced mGluR-dependent LTD and behavioral abnormalities caused by Cyfip1 haploinsufficiency (Bozdagi et al., 2012), similar to the phenotype observed in Fmr1 KO mice (Bear et al., 2004).”

    From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Bozdagi et al., 2012

  • CYFIP1 has a vital role in the local regulation of spine actin dynamics via WAVE and Arp2/3.

    “In addition to previous functions described for CYFIP1 in the regulation of mRNA translation in dendrites and mGluR-long-term depression, our results suggest that CYFIP1 also has a vital role in the local regulation of spine actin dynamics via WAVE and Arp2/3.32,35”

    From The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines (2014) · cites this paper as [35]

    The Introduction and Discussion describe CYFIP1’s role in synaptic translation and mGluR-dependent long-term depression, but do not address local spine actin regulation through WAVE and Arp2/3. Searches for WAVE, Arp2/3, and spine actin dynamics found no passage supporting that specific claim. In the citing sentence, the actin claim is framed as the citing authors’ own result. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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References 49 · Cited by 97

Research works printed but not linked: 41

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Authors
Bozdagi, O., Sakurai, T., Dorr, N., Pilorge, M., Takahashi, N., & Buxbaum, J. D.
Affiliations
Icahn School of Medicine at Mount Sinai (US)
Corresponding author
Buxbaum, Joseph D.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-08-10
Volume
7
Issue
8
Pages
e42422
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0042422
PMC
PMC3416859
OpenAlex
W2008718844
Cited by
97
References
49
Citations by year
2026: 1 · 2025: 3 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 8 · 2020: 16 · 2019: 11 · 2018: 9 · 2017: 6 · 2016: 8 · 2015: 7 · 2014: 9 · 2013: 8 · 2012: 1
FWCI
4.82
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
CYFIP1, haploinsufficiency, FMRP, FMR1 gene, copy number variation, 15q11.2, fragile X syndrome, metabotropic glutamate receptors, long-term depression, mGluR5, mGluR1, protein synthesis, synaptic plasticity, passive avoidance, extinction, autism spectrum disorder, intellectual disability, neuropsychiatric disorders, mTOR, rapamycin, hippocampus
MeSH terms
Animals, Behavior, Animal, Disease Models, Animal, Fragile X Syndrome, Genotype, Male, Methoxyhydroxyphenylglycol, Nerve Tissue Proteins, Phenotype, Protein Biosynthesis, Receptors, Glutamate, Long-Term Potentiation, Mice, Knockout, Excitatory Amino Acid Antagonists, Gene Order, Long-Term Synaptic Depression, Adaptor Proteins, Signal Transducing, Mice, DNA Copy Number Variations, Haploinsufficiency

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