A neuroligin-3 mutation implicated in autism causes abnormal aggression and increases repetitive behavior in mice.
A neuroligin-3 mutation implicated in autism causes abnormal aggression and increases repetitive behavior in mice.
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DOI：
10.1186/s13229-015-0055-7
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发表时间：
2015
期刊：
影响因子：
6.2
通讯作者：
Hannan AJ
中科院分区：
文献类型：
--
作者：
Burrows EL;Laskaris L;Koyama L;Churilov L;Bornstein JC;Hill-Yardin EL;Hannan AJ
攻击行为在自闭症谱系障碍 (ASD) 患者中很常见，其核心症状是社交沟通障碍和重复行为。利培酮是一种非典型抗精神病药，广泛用于治疗自闭症谱系障碍患者的攻击行为。为了了解这些具有挑战性的行为的神经生物学基础，需要对动物模型中的行为内表型进行彻底的表征。我们研究了 Neuroligin-3 (NL3) 中含有 ASD 相关 R451C（精氨酸到半胱氨酸残基 451 取代）突变的小鼠的攻击行为。此外，我们试图验证 NL3R451C 突变小鼠的社交互动障碍并评估嗅觉、焦虑以及重复和限制性行为。我们发现 NL3R451C 突变小鼠的攻击行为显着升高。利培酮治疗将这种攻击性降低至野生型（WT）水平。还研究了青少年和成年的社交互动，并在青少年 NL3R451C 小鼠中观察到互动启动的细微差异。没有观察到嗅觉辨别或焦虑的基因型差异，这表明攻击性并不依赖于嗅觉、压力反应或社会偏好的改变。我们还描述了通过临床相关对象探索任务评估的 NL3R451C 小鼠的重复行为。 NL3R451C 小鼠中与临床特征一致的异常攻击行为和其他行为表型的存在增强了该自闭症谱系障碍模型的表面有效性。此外，我们通过利培酮逆转攻击性表型证明了该模型的预测有效性。这是首次证明利培酮可以改善自闭症动物模型的攻击性，并将为自闭症谱系障碍异常行为的神经生物学机制和治疗研究提供信息。本文的在线版本 (doi:10.1186/s13229-015-0055-7) 包含补充材料，可供授权用户使用。
Aggression is common in patients with autism spectrum disorders (ASD) along with the core symptoms of impairments in social communication and repetitive behavior. Risperidone, an atypical antipsychotic, is widely used to treat aggression in ASD. In order to understand the neurobiological underpinnings of these challenging behaviors, a thorough characterisation of behavioral endophenotypes in animal models is required. We investigated aggression in mice containing the ASD-associated R451C (arginine to cysteine residue 451 substitution) mutation in neuroligin-3 (NL3). Furthermore, we sought to verify social interaction impairments and assess olfaction, anxiety, and repetitive and restrictive behavior in NL3R451C mutant mice. We show a pronounced elevation in aggressive behavior in NL3R451C mutant mice. Treatment with risperidone reduced this aggression to wild-type (WT) levels. Juvenile and adult social interactions were also investigated, and subtle differences in initiation of interaction were seen in juvenile NL3R451C mice. No genotype differences in olfactory discrimination or anxiety were observed indicating that aggression was not dependent on altered olfaction, stress response, or social preference. We also describe repetitive behavior in NL3R451C mice as assessed by a clinically relevant object exploration task. The presence of aberrant aggression and other behavioral phenotypes in NL3R451C mice consistent with clinical traits strengthen face validity of this model of ASD. Furthermore, we demonstrate predictive validity in this model through the reversal of the aggressive phenotype with risperidone. This is the first demonstration that risperidone can ameliorate aggression in an animal model of ASD and will inform mechanistic and therapeutic research into the neurobiology underlying abnormal behaviors in ASD. The online version of this article (doi:10.1186/s13229-015-0055-7) contains supplementary material, which is available to authorized users.