Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction
SCIE
SCOPUS
- Title
- Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction
- Authors
- Lee S.-H.; Zhang Y.; Park J.; Kim B.; Kim Y.; Lee S.H.; Kim G.H.; Huh Y.H.; Lee B.; Kim Y.; Lee Y.; Kim J.Y.; Kang H.; Choi S.-Y.; Jang S.; Li Y.; Kim S.; Jin C.; Pang K.; Kim E.; Lee Y.; Kim H.; Kim E.; Choi J.H.; Kim J.; Lee K.J.; Choi S.-Y.; Han K.
- Date Issued
- 2020-09
- Publisher
- NLM (Medline)
- Abstract
- 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 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 on Cyfip2+/- mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses on Cyfip2+/- prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with viral 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. Viral-mediated CYFIP2 reduction 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 lithium-mediated amelioration of neurobehavioral phenotypes in adult Cyfip2+/- mice, which can be implicated in CYFIP2-associated brain disorders. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
- URI
- https://oasis.postech.ac.kr/handle/2014.oak/106692
- DOI
- 10.1002/ana.25827
- ISSN
- 0364-5134
- Article Type
- Article
- Citation
- Annals of neurology, vol. 88, no. 3, page. 526 - 543, 2020-09
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