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.
ABSTRACTRecent molecular genetic studies have suggested that two members of the cytoplasmic FMR1-interacting protein (CYFIP) gene family, CYFIP1 and CYFIP2, are causally associated with several bra...
#2Shuang Liao(CQMU: Chongqing Medical University)H-Index: 1
Last. Li Jiang(CQMU: Chongqing Medical University)H-Index: 5
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RATIONALE: Early infantile epileptic encephalopathy (EIEE) 65 was recently shown to be caused by the cytoplasmic FMRP interacting protein 2 (CYFIP2) mutation. To date, only 5 cases have been reported in two articles, and all the outcomes in all cases were poor. PATIENT CONCERNS: In this study, we reported an 8-month-old girl with a 1 month-long history of seizures and developmental delay. Over 1 month later, she developed epileptic spasms in clusters with hypsarrhythmia on electroencephalography...
#2Adrian C Lo(UNIL: University of Lausanne)H-Index: 2
Last. Claudia Bagni(UNIL: University of Lausanne)H-Index: 51
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Copy-number variants of the CYFIP1 gene in humans have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), two neuropsychiatric disorders characterized by defects in brain connectivity. Here, we show that CYFIP1 plays an important role in brain functional connectivity and callosal functions. We find that Cyfip1-heterozygous mice have reduced functional connectivity and defects in white matter architecture, similar to phenotypes found in patients with ASD, SCZ and other neurop...
The auditory steady-state response (ASSR) has been used to detect auditory processing deficits in patients with psychiatric disorders. However, the methodology of ASSR recording from the brain surface has not been standardized in preclinical studies, limiting its use as a translational biomarker. The sites of maximal ASSR in humans are the vertex and/or middle frontal area, although it has been suggested that the auditory cortex is the source of the ASSR. We constructed and validated novel metho...
: The cytoplasmic FMR1-interacting protein family (CYFIP1 and CYFIP2) are evolutionarily conserved proteins originally identified as binding partners of the fragile X mental retardation protein (FMRP), a messenger RNA (mRNA)-binding protein whose loss causes the fragile X syndrome. Moreover, CYFIP is a key component of the heteropentameric WAVE regulatory complex (WRC), a critical regulator of neuronal actin dynamics. Therefore, CYFIP may play key roles in regulating both mRNA translation and ac...
Last. Jee Hyun Choi(KIST: Korea Institute of Science and Technology)H-Index: 20
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High-density electroencephalographic (hdEEG) recordings are widely used in human studies to determine spatio-temporal patterns of cortical electrical activity. How these patterns of activity are modulated by subcortical arousal systems is poorly understood. Here, we couple selective optogenetic stimulation of a defined subcortical cell-type, basal forebrain (BF) parvalbumin (PV) neurons, with hdEEG recordings in mice (Opto-hdEEG). Stimulation of BF PV projection neurons preferentially generated ...
Last. Josef T. Kittler(UCL: University College London)H-Index: 56
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Summary Altered excitatory/inhibitory (E/I) balance is implicated in neuropsychiatric and neurodevelopmental disorders, but the underlying genetic etiology remains poorly understood. Copy number variations in CYFIP1 are associated with autism, schizophrenia, and intellectual disability, but its role in regulating synaptic inhibition or E/I balance remains unclear. We show that CYFIP1, and the paralog CYFIP2, are enriched at inhibitory postsynaptic sites. While CYFIP1 or CYFIP2 upregulation incre...
CYFIP2, encoding the evolutionary highly conserved cytoplasmic FMRP interacting protein 2, has previously been proposed as a candidate gene for intellectual disability and autism because of its important role linking FMRP-dependent transcription regulation and actin polymerization via the WAVE regulatory complex (WRC). Recently, de novo variants affecting the amino acid p.Arg87 of CYFIP2 were reported in four individuals with epileptic encephalopathy. We here report 12 independent patients harbo...
Deletions in the 15q11.2 region of the human genome are associated with neurobehavioral deficits, and motor development delay, as well as in some cases, symptoms of autism or schizophrenia. The cytoplasmic FMRP-interacting protein 1 (CYFIP1) is one of the four genes contained within this locus and has been associated with other genetic forms of autism spectrum disorders (ASD). In mice, Cyfip1 haploinsufficiency leads to alteration of dendritic spine morphology and defects in synaptic plasticity,...
In humans, the cytoplasmic FMR1 interacting protein (CYFIP) family is composed of CYFIP1 and CYFIP2. Despite their high similarity and shared interaction with many partners, CYFIP1 and CYFIP2 act at different points in cellular processes. CYFIP1 and CYFIP2 have different expression levels in human tissues, and knockout animals die at different time points of development. CYFIP1, similar to CYFIP2, acts in the WAVE regulatory complex (WRC) and plays a role in actin dynamics through the activation...
The cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2) gene is associated with epilepsy, intellectual disability (ID), and developmental delay, suggesting its critical role in proper neuronal development and function. CYFIP2 is involved in regulating cellular actin dynamics and also interacts with RNA-binding proteins. However, the adult brain function of CYFIP2 remains unclear because investigations thus far are limited to Cyfip2 heterozygous (Cyfip2+/- ) mice owin...
Variants of the cytoplasmic FMR1-interacting protein (CYFIP) gene family, CYFIP1 and CYFIP2, are associated with numerous neurodevelopmental and neuropsychiatric disorders. According to several studies, CYFIP1 regulates the development and function of both pre- and post-synapses in neurons. Furthermore, various studies have evaluated CYFIP2 functions in the postsynaptic compartment, such as regulating dendritic spine morphology; however, no study has evaluated whether and how CYFIP2 affects pres...