Haploinsufficiency of Cyfip1 Produces Fragile X-Like Phenotypes in Mice

Ozlem Bozdagi,Nathan Dorr,Joseph D Buxbaum,Nagahide Takahashi,Marion Pilorge,Takeshi Sakurai,Ted M Dawson

doi:10.1371/journal.pone.0042422

Ozlem Bozdagi, Nathan Dorr + Show 5 more

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https://doi.org/10.1371/journal.pone.0042422

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Journal: PloS one	Publication Date: Aug 10, 2012
Citations: 101	License type: CC BY 4.0

Affiliation: Icahn School of Medicine at Mount Sinai

Abstract

BackgroundCopy 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 FindingsWe 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/SignificanceThese 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.

Highlights

Copy number variation (CNV) in the 15q11.2 (BP1–BP2) region represent replicated risk factors for schizophrenia, epilepsy, intellectual disability, developmental delay, and autism [1,2,3,4,5]
We measured gene expression by quantitative PCR, and found that Cyfip1 mRNA is reduced by 50% (Fig. 1C)
Based on the evidence for 15q11.2 deletion and duplications in psychiatric phenotypes and the presence of the fragile X mental retardation protein (FMRP)-binding protein CYFIP1 in this interval, we carried out functional analyses of Cyfip1

Summary

Introduction

CNVs in the 15q11.2 (BP1–BP2) region represent replicated risk factors for schizophrenia, epilepsy, intellectual disability, developmental delay, and autism [1,2,3,4,5]. The CNV includes a minimal 0.3 Mb region that encompasses five refseq genes (TUBGCP5, CYFIP1, NIPA2, NIPA1, and WHAMML1, see [8]) and increases risk for schizophrenia by 2–4 fold. This interval has already been of interest in psychiatric disorders because of its involvement in autism spectrum disorders (ASD) involving duplications of 15q11-q13 and Prader-Willi and Angelman syndromes [9]. In the current study we studied the function of Cyfip in synaptic physiology and behavior, using mice with a disruption of the Cyfip gene

Methods

Results

Conclusion