Haploinsufficiency of Cyfip1 produces fragile X-like phenotypes in mice.
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.


RESULTS
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
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.
Seaver Autism Center for Research and Treatment, Mount Sinai School of Medicine, New York, New York, United States of America.
Ozlem
O
Bozdagi
Takeshi
T
Sakurai
Nathan
N
Dorr
Marion
M
Pilorge
Nagahide
N
Takahashi
Joseph D
JD
Buxbaum
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001522:Behavior, Animal; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005600:Fragile X Syndrome / Q000235:genetics*; D023061:Gene Order; D005838:Genotype; D057895:Haploinsufficiency / Q000235:genetics*; D017774:Long-Term Potentiation / Q000187:drug effects / Q000235:genetics; D036881:Long-Term Synaptic Depression / Q000187:drug effects / Q000235:genetics; D008297:Male; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D014176:Protein Biosynthesis / Q000235:genetics; D017470:Receptors, Glutamate / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C115472:Cyfip1 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D017470:Receptors, Glutamate; D008734:Methoxyhydroxyphenylglycol; C010117:3,4-dihydroxyphenylglycol