Haploinsufficiency of Cyfip2 Causes Lithium‐Responsive Prefrontal Dysfunction
| العنوان: | Haploinsufficiency of Cyfip2 Causes |
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| المؤلفون: | Bowon Kim, Bokyoung Lee, Yang Hoon Huh, Sang-Hoon Lee, Seil Jang, Jin Yong Kim, Kihoon Han, Jeong Jin Kim, Yinhua Zhang, Kaifang Pang, Yan Li, Yangsik Kim, Chunmei Jin, Hyun Kim, Yoontae Lee, Shinhyun Kim, Seung-Hyun Lee, Jee Hyun Choi, Su Yeon Choi, Yoonhee Kim, Kea Joo Lee, Eunjoon Kim, Gyu Hyun Kim, Yeunkum Lee, Jina Park, Se-Young Choi, Eunjeong Kim, Hyojin Kang |
| المصدر: | Annals of Neurology. 88:526-543 |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Dendritic spine, Prefrontal Cortex, Haploinsufficiency, Biology, Filamentous actin, Mice, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Seizures, medicine, Animals, Prefrontal cortex, Adaptor Proteins, Signal Transducing, Neurons, Behavior, Animal, medicine.disease, Mice, Mutant Strains, Potassium channel, Electrophysiology, 030104 developmental biology, Neurology, CYFIP2, Lithium Compounds, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery |
| الوصف: | OBJECTIVE Genetic variants of the cytoplasmic FMR1-interacting protein 2 (CYFIP2) encoding an actin-regulatory protein are associated with brain disorders, including intellectual disability and epilepsy. However, specific in vivo neuronal defects and potential treatments for CYFIP2-associated brain disorders remain largely unknown. Here, we characterized Cyfip2 heterozygous (Cyfip2+/- ) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of the Cyfip2+/- mice and specified a neuronal function mediating its efficacy. METHODS We performed behavioral analyses of Cyfip2+/- mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses of Cyfip2+/- prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. RESULTS Adult Cyfip2+/- mice exhibited lithium-responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adult Cyfip2+/- PFC that was restricted to layer 5 (L5) neurons. Consistently, adult Cyfip2+/- mice showed increased seizure susceptibility and auditory steady-state responses from the cortical electroencephalographic recordings. Among the identified prefrontal defects, lithium selectively normalized the hyperexcitability of Cyfip2+/- L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adult Cyfip2+/- PFC. Virus-mediated reduction of CYFIP2 in the PFC was sufficient to induce L5 hyperexcitability and lithium-responsive abnormal behavior. INTERPRETATION These results suggest that L5-specific prefrontal dysfunction, especially hyperexcitability, underlies both the pathophysiology and the lithium-mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/- mice, which can be implicated in CYFIP2-associated brain disorders. ANN NEUROL 2020;88:526-543. |
| تدمد: | 1531-8249 0364-5134 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3023b2f40fb19f7772d9179c4709a080 https://doi.org/10.1002/ana.25827 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....3023b2f40fb19f7772d9179c4709a080 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15318249 03645134 |
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