Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction
© 2020 American Neurological Association..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:88 |
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| Enthalten in: |
Annals of neurology - 88(2020), 3 vom: 01. Sept., Seite 526-543 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lee, Seung-Hyun [VerfasserIn] |
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| Links: |
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| Themen: |
Adaptor Proteins, Signal Transducing |
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| Anmerkungen: |
Date Completed 04.01.2021 Date Revised 04.01.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/ana.25827 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM311410693 |
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| 041 | |a eng | ||
| 100 | 1 | |a Lee, Seung-Hyun |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 04.01.2021 | ||
| 500 | |a Date Revised 04.01.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 American Neurological Association. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Adaptor Proteins, Signal Transducing |2 NLM | |
| 650 | 7 | |a Cyfip2 protein, mouse |2 NLM | |
| 650 | 7 | |a Lithium Compounds |2 NLM | |
| 700 | 1 | |a Zhang, Yinhua |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Jina |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Bowon |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Yangsik |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Sang Hoon |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Gyu Hyun |e verfasserin |4 aut | |
| 700 | 1 | |a Huh, Yang Hoon |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Bokyoung |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Yoonhee |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Yeunkum |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Jin Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, Hyojin |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Su-Yeon |e verfasserin |4 aut | |
| 700 | 1 | |a Jang, Seil |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yan |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Shinhyun |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, Chunmei |e verfasserin |4 aut | |
| 700 | 1 | |a Pang, Kaifang |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Eunjeong |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Yoontae |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Hyun |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Eunjoon |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Jee Hyun |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Jeongjin |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Kea Joo |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Se-Young |e verfasserin |4 aut | |
| 700 | 1 | |a Han, Kihoon |e verfasserin |4 aut | |
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