CYFIP1 Dosages Exhibit Divergent Behavioral Impact via Diametric Regulation of NMDA Receptor Complex Translation in Mouse Models of Psychiatric Disorders
| Autor: | Valina L. Dawson, Guo Li Ming, Kimberly M. Christian, Stephanie J. Temme, Weidong Li, Stephen M. Eacker, Kuei Sen Hsu, Stefan Canzar, Ki Jun Yoon, Francisca Rojas Ringeling, Ted M. Dawson, Ha Nam Nguyen, Bo Xiao, Paul F. Worley, Yu Ting Lin, Namshik Kim, Hongjun Song, Ying Zhou |
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| Rok vydání: | 2022 |
| Předmět: |
0301 basic medicine
N-Methylaspartate DNA Copy Number Variations Autism Spectrum Disorder RNA-binding protein Biology Receptors N-Methyl-D-Aspartate Gene dosage Mice 03 medical and health sciences 0302 clinical medicine Postsynaptic potential mental disorders medicine Animals RNA Messenger Copy-number variation Biological Psychiatry Adaptor Proteins Signal Transducing Messenger RNA Mental Disorders Translation (biology) medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology Schizophrenia RNA NMDA receptor Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Biological Psychiatry. 92:815-826 |
| ISSN: | 0006-3223 |
| DOI: | 10.1016/j.biopsych.2021.04.023 |
| Popis: | Background Gene dosage imbalance caused by copy number variations (CNVs) is a prominent contributor to brain disorders. In particular, 15q11.2 CNV duplications and deletions have been associated with autism spectrum disorder and schizophrenia, respectively. The mechanism underlying these diametric contributions remains unclear. Methods We established both loss-of-function and gain-of-function mouse models of Cyfip1, one of four genes within 15q11.2 CNVs. To assess the functional consequences of altered CYFIP1 levels, we performed systematic investigations on behavioral, electrophysiological, and biochemical phenotypes in both mouse models. In addition, we utilized RNA immunoprecipitation sequencing (RIP-seq) analysis to reveal molecular targets of CYFIP1 in vivo. Results Cyfip1 loss-of-function and gain-of function mouse models exhibited distinct and shared behavioral abnormalities related to autism spectrum disorder and schizophrenia. RIP-seq analysis identified messenger RNA targets of CYFIP1 in vivo, including postsynaptic NMDA receptor (NMDAR) complex components. In addition, these mouse models showed diametric changes in levels of postsynaptic NMDAR complex components at synapses because of dysregulated protein translation, resulting in bidirectional alteration of NMDAR-mediated signaling. Importantly, pharmacological balancing of NMDAR signaling in these mouse models with diametric Cyfip1 dosages rescues behavioral abnormalities. Conclusions CYFIP1 regulates protein translation of NMDAR and associated complex components at synapses to maintain normal synaptic functions and behaviors. Our integrated analyses provide insight into how gene dosage imbalance caused by CNVs may contribute to divergent neuropsychiatric disorders. |
| Databáze: | OpenAIRE |
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