Haploinsufficiency of Cyfip2 Causes Lithium-Responsive Prefrontal Dysfunction

Authors
Lee, Seung-HyunZhang, YinhuaPark, JinaKim, BowonKim, YangsikLee, Sang HoonKim, Gyu HyunHuh, Yang HoonLee, BokyoungKim, YoonheeLee, YeunkumKim, Jin YongKang, HyojinChoi, Su-YeonJang, SeilLi, YanKim, ShinhyunJin, ChunmeiPang, KaifangKim, EunjeongLee, YoontaeKim, HyunKim, EunjoonChoi, Jee HyunKim, JeongjinLee, Kea JooChoi, Se-YoungHan, Kihoon
Issue Date
2020-09
Publisher
WILEY
Citation
ANNALS OF NEUROLOGY, v.88, no.3, pp.526 - 543
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 forCYFIP2-associated brain disorders remain largely unknown. Here, we characterizedCyfip2heterozygous (Cyfip2(+/-)) mice to understand their neurobehavioral phenotypes and the underlying pathological mechanisms. Furthermore, we examined a potential treatment for such phenotypes of theCyfip2(+/-)mice and specified a neuronal function mediating its efficacy. Methods We performed behavioral analyses ofCyfip2(+/-)mice. We combined molecular, ultrastructural, and in vitro and in vivo electrophysiological analyses ofCyfip2(+/-)prefrontal neurons. We also selectively reduced CYFIP2 in the prefrontal cortex (PFC) of mice with virus injections. Results AdultCyfip2(+/-)mice exhibited lithium-responsive abnormal behaviors. We found increased filamentous actin, enlarged dendritic spines, and enhanced excitatory synaptic transmission and excitability in the adultCyfip2(+/-)PFC that was restricted to layer 5 (L5) neurons. Consistently, adultCyfip2(+/-)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 ofCyfip2(+/-)L5 neurons. RNA sequencing revealed reduced expression of potassium channel genes in the adultCyfip2(+/-)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 adultCyfip2(+/-)mice, which can be implicated inCYFIP2-associated brain disorders. ANN NEUROL 2020
Keywords
DENDRITIC SPINES; OSCILLATIONS; PROTEINS; CHANNELS; INSIGHTS; BEHAVIOR; DELETION; DENSITY; NETWORK; AUTISM; DENDRITIC SPINES; OSCILLATIONS; PROTEINS; CHANNELS; INSIGHTS; BEHAVIOR; DELETION; DENSITY; NETWORK; AUTISM
ISSN
0364-5134
URI
https://pubs.kist.re.kr/handle/201004/118174
DOI
10.1002/ana.25827
Appears in Collections:
KIST Article > 2020
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