Deficiency of calretinin in prefrontal cortex causes behavioral deficits relevant to autism spectrum disorder in mice.

IF 2.9 3区 医学 Q2 NEUROSCIENCES
Yaodong Zhang, Xiaotong Zhao, Chao Gao, Shengli Shi, Mengyuan Chen, Bin Guo, Shunan Hu, Daoqi Mei, Xujun Duan, Xiaona Wang
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Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by core symptoms including deficits in social interaction, repetitive and stereotyped behaviors, along with higher levels of anxiety and cognitive impairments. Previous studies demonstrate pronounced reduced density of calretinin (CR)-expressing GABAergic interneurons in both ASD patients and animal models. The object of the current study was to determine the role of CR in ASD-relevant behavioral aberrations. Herein, the mRNA and protein levels of CR in the prefrontal cortex (PFC) of mouse model of ASD based on prenatal exposure to valproic acid (VPA) were determined by qRT-PCR and Western blot analysis, respectively. Moreover, the behavioral abnormalities in naive mice with CR deficiency mediated by recombinant adeno-associated virus (rAAV) were evaluated in a comprehensive testing battery including social interaction, marble burying, self-grooming, open-field, elevated plus maze and novel object recognition tests. Furthermore, the action potential changes caused by CR deficiency were examined in neurons within the PFC in naive mouse. The results show that the mRNA and protein levels of PFC CR of VPA-induced mouse ASD model were reduced. Concomitantly, mice with CR knockdown displayed ASD-like behavioral aberrations, such as social impairments, elevated stereotypes, anxiety and memory defects. Intriguingly, patch-clamp recordings revealed that CR knockdown provoked decreased neuronal excitability by increasing action potential discharge frequencies together with decreased action potential threshold and rheobase. Our findings support a notion that CR knockdown might contribute to ASD-like phenotypes, with the pathogenesis most likely stemming from increased neuronal excitability.

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小鼠前额皮质钙化蛋白缺乏导致与自闭症谱系障碍相关的行为缺陷。
自闭症谱系障碍(ASD)是一种神经发育障碍,其核心症状包括社交互动缺陷、重复和刻板行为,以及更高水平的焦虑和认知障碍。先前的研究表明,在ASD患者和动物模型中,表达gaba能的calretinin (CR)的中间神经元密度明显降低。本研究的目的是确定CR在asd相关行为异常中的作用。本研究采用qRT-PCR和Western blot方法分别检测基于产前丙戊酸(VPA)暴露的ASD小鼠模型前额叶皮质(PFC) CR mRNA和蛋白水平。此外,我们还对重组腺相关病毒(rAAV)介导的CR缺乏小鼠的行为异常进行了综合测试,包括社会互动、大理石掩埋、自我梳理、野外、高架迷宫和新物体识别测试。此外,我们还检测了未成熟小鼠PFC内神经元中CR缺乏引起的动作电位变化。结果表明,vpa诱导的小鼠ASD模型PFC CR mRNA和蛋白水平降低。与此同时,CR基因敲低的小鼠表现出类似asd的行为异常,如社交障碍、刻板印象升高、焦虑和记忆缺陷。有趣的是,膜片钳记录显示,通过增加动作电位放电频率以及降低动作电位阈值和流变酶,CR敲低引起神经元兴奋性降低。我们的研究结果支持了一种观点,即CR敲低可能有助于asd样表型,其发病机制很可能源于神经元兴奋性增加。
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来源期刊
Molecular Brain
Molecular Brain NEUROSCIENCES-
CiteScore
7.30
自引率
0.00%
发文量
97
审稿时长
>12 weeks
期刊介绍: Molecular Brain is an open access, peer-reviewed journal that considers manuscripts on all aspects of studies on the nervous system at the molecular, cellular, and systems level providing a forum for scientists to communicate their findings. Molecular brain research is a rapidly expanding research field in which integrative approaches at the genetic, molecular, cellular and synaptic levels yield key information about the physiological and pathological brain. These studies involve the use of a wide range of modern techniques in molecular biology, genomics, proteomics, imaging and electrophysiology.
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