title: Parental origin impairment of synaptic functions and behaviors in cytoplasmic FMRP interacting protein 1 (Cyfip1) deficient mice.
abstract: CYFIP1 maps to the interval between proximal breakpoint 1 (BP1) and breakpoint 2 (BP2) of chromosomal 15q11-q13 deletions that are implicated in the Angelman (AS) and Prader-Willi syndrome (PWS). There is only one breakpoint (BP3) at the distal end of deletion. CYFIP1 is deleted in AS patients with the larger class I deletion (BP1 to BP3) and the neurological presentations in these patients are more severe than that of patients with class II (BP2 to BP3) deletion. The haploinsufficiency of CYFIP1 is hypothesized to contribute to more severe clinical presentations in class I AS patients. The expression of CYFIP1 is suggested to be bi-allelic in literature but the possibility of parental origin of expression is not completely excluded. We generated and characterized Cyfip1 mutant mice. Homozygous Cyfip1 mice were early embryonic lethal. However, there was a parental origin specific effect between paternal Cyfip1 deficiency (m+/p-) and maternal deficiency (m-/p+) on both synaptic transmissions and behaviors in hippocampal CA1 synapses despite no evidence supporting the parental origin difference for the expression. Both m-/p+ and m+/p- showed the impaired input-output response and paired-pulse facilitation. While the long term-potentiation and group I mGluR mediated long term depression induced by DHPG was not different between Cyfip1 m-/p+ and m+/p- mice, the initial DHPG induced response was significantly enhanced in m-/p+ but not in m+/p- mice. m+/p- but not m-/p+ mice displayed increased freezing in cued fear conditioning and abnormal transitions in zero-maze test. The impaired synaptic transmission and behaviors in haploinsufficiency of Cyfip1 mice provide the evidence supporting the role of CYFIP1 modifying the clinical presentation of class I AS patients and in human neuropsychiatric disorders.
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, United States.
authors.forename: Leeyup
authors.initials: L
authors.lastname: Chung
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, United States.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC 27710, United States.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Towers
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, United States.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Cell Biology, Duke University School of Medicine, Durham, NC 27710, United States.
authors.forename: Il Hwan
authors.initials: IH
authors.lastname: Kim
authors.affiliation: Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, United States; University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC 27710, United States; Department of Neurobiology, Duke University School of Medicine, Durham, NC 27710, United States. Electronic address: yong-hui.jiang@duke.edu.
authors.forename: Yong-hui
authors.initials: YH
authors.lastname: Jiang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005239:Fear / Q000502:physiology* / Q000523:psychology*; D005260:Female; D040582:Inheritance Patterns / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics*; D011218:Prader-Willi Syndrome / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C115472:Cyfip1 protein, mouse; D009419:Nerve Tissue Proteins
keywords: Parental origin