Phenotypic Characterization of Nonsocial Behavioral Impairment in Neurexin 1α Knockout Rats
Phenotypic Characterization of Nonsocial Behavioral Impairment in Neurexin 1α Knockout Rats
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DOI：
10.1037/bne0000024
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发表时间：
2015-02-01
影响因子：
1.9
通讯作者：
Gilmour, Gary
中科院分区：
文献类型：
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作者：
Esclassan, Frederic;Francois, Jennifer;Gilmour, Gary
神经素是神经元突触前蛋白，在突触形成的调解中起关键作用。在自闭症谱系障碍（ASD）患者中观察到神经素-1基因（NRXN1, 2p16.3）的杂合性部分缺失。nrxn1 - α敲除（KO）小鼠表现出的行为障碍类似于一些核心的ASD症状，如社交障碍和不灵活/刻板印象。目前，对认知功能的全面评估尚未完成。在Sprague Dawley背景下含有nrnx1 - α基因双等位基因缺失的大鼠与同窝野生型大鼠进行了一系列任务比较，这些任务旨在测试ASD和其他神经发育障碍中被破坏的功能域，包括感觉知觉（脉冲前抑制）、注意力（潜在抑制）、联想学习（工具和巴甫洛夫条件反射）和记忆（奖励交替T迷宫和空间辨别）。研究发现NRXN1 α - KO大鼠存在大量且持续的非社会缺陷，包括多动症、简单工具学习缺陷、潜在抑制和空间依赖学习。尽管存在夸张的惊吓反应，但没有观察到感觉运动门控的缺陷。虽然KO动物也能够学习简单的巴甫洛夫条件反射辨别，但它们确实表现出潜在抑制受损。NRXN1 α KO大鼠在几个区域存在明显的损伤，这清楚地表明，非社会认知缺陷也可以在ASD动物模型中测量。根据创新药物计划的欧洲自闭症干预：开发新药物项目的多中心研究计划，在临床和临床前对这些缺陷进行进一步的探索，可能有助于更好地了解与ASD有关的大脑回路，从而为推进新疗法开辟新的途径。
Neurexins are neuronal presynaptic proteins that play a key role in mediation of synapse formation. Heterozygous partial deletions in the neurexin-1 gene (NRXN1, 2p16.3) have been observed in autism spectrum disorder (ASD) patients. NRXN1-alpha knockout (KO) mice present behavioral impairments that resemble some of the core ASD symptoms of social impairment and inflexibility/stereotypy. At present, a thorough assessment of cognitive function has yet to be completed. Rats, containing a biallelic deletion of the NRNX1-alpha gene on a Sprague Dawley background were compared to littermate wild types across a range of tasks designed to test functional domains disrupted in ASD and other neurodevelopmental disorders, including sensory perception (prepulse inhibition), attention (latent inhibition), associative learning (instrumental and Pavlovian conditioning), and memory (rewarded alternation T maze and spatial discrimination). NRXN1 alpha KO rats were found to present with large and persistent nonsocial deficits, including hyperactivity, deficits in simple instrumental learning, latent inhibition, and spatial-dependent learning. No deficit in sensorimotor gating was observed, despite the presence of an exaggerated startle response. Although KO animals were also able to learn a simple Pavlovian conditioning discrimination, they did display impaired latent inhibition. The presence of pronounced impairments in several domains in NRXN1 alpha KO rats clearly suggests that nonsocial cognitive deficits can also be measured in an animal model of ASD. Further exploration of those deficits, both clinically and preclinically, as planned in the Innovative Medicines Initiative's European Autism Interventions: A Multicenter Study for Developing New Medications program, may help to better understand the brain circuitry involved in ASD and therefore open new avenues to advance novel therapies.