Autism-relevant social abnormalities and cognitive deficits in engrailed-2 knockout mice.
Autism-relevant social abnormalities and cognitive deficits in engrailed-2 knockout mice.
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DOI：
10.1371/journal.pone.0040914
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Crawley JN
中科院分区：
文献类型：
--
作者：
Brielmaier J;Matteson PG;Silverman JL;Senerth JM;Kelly S;Genestine M;Millonig JH;DiCicco-Bloom E;Crawley JN
ENGRAILED 2 (En2) 是一种同源盒转录因子，在啮齿动物后脑和小脑的早期发育和连接中充当模式基因，并调节单胺能通路的神经发生和发育。为了进一步了解 En2 的神经生物学功能，我们对 En2 野生型小鼠进行了神经解剖表达谱分析。 RTQPCR 测定表明，En2 在成人大脑结构中表达，包括体感皮层、海马、纹状体、丘脑、下丘脑和脑干。人类遗传学研究表明 EN2 与自闭症有关。为了确定 En2 突变对小鼠行为的影响，包括与自闭症潜在相关的结果，我们对社交、沟通、重复和认知行为进行了全面的表型分析。 En2无效突变体在青少年和成年时表现出在相互社交互动方面的严重缺陷，并且在成年人中缺乏社交能力，这在两个独立的队列中得到了复制。 En2 无效突变体的恐惧调节和水迷宫学习受到损害。在 En2 无效突变体中检测到强迫游泳测试中的高度不动、前脉冲抑制降低、轻度运动协调障碍和握力降低。在社会背景下的超声波发声测量中没有发现基因型差异，也没有观察到刻板或重复的行为。发育里程碑、总体健康状况、嗅觉能力、探索性运动活动、焦虑样行为和疼痛反应在不同基因型之间没有差异，表明在 En2 无效突变体中检测到的行为异常并非由物理或程序混杂所致。我们的研究结果为 En2 在复杂行为中的作用提供了新的见解，并表明 En2 信号传导紊乱可能导致以社交和认知缺陷为特征的神经精神疾病，包括自闭症谱系障碍。
ENGRAILED 2 (En2), a homeobox transcription factor, functions as a patterning gene in the early development and connectivity of rodent hindbrain and cerebellum, and regulates neurogenesis and development of monoaminergic pathways. To further understand the neurobiological functions of En2, we conducted neuroanatomical expression profiling of En2 wildtype mice. RTQPCR assays demonstrated that En2 is expressed in adult brain structures including the somatosensory cortex, hippocampus, striatum, thalamus, hypothalamus and brainstem. Human genetic studies indicate that EN2 is associated with autism. To determine the consequences of En2 mutations on mouse behaviors, including outcomes potentially relevant to autism, we conducted comprehensive phenotyping of social, communication, repetitive, and cognitive behaviors. En2 null mutants exhibited robust deficits in reciprocal social interactions as juveniles and adults, and absence of sociability in adults, replicated in two independent cohorts. Fear conditioning and water maze learning were impaired in En2 null mutants. High immobility in the forced swim test, reduced prepulse inhibition, mild motor coordination impairments and reduced grip strength were detected in En2 null mutants. No genotype differences were found on measures of ultrasonic vocalizations in social contexts, and no stereotyped or repetitive behaviors were observed. Developmental milestones, general health, olfactory abilities, exploratory locomotor activity, anxiety-like behaviors and pain responses did not differ across genotypes, indicating that the behavioral abnormalities detected in En2 null mutants were not attributable to physical or procedural confounds. Our findings provide new insight into the role of En2 in complex behaviors and suggest that disturbances in En2 signaling may contribute to neuropsychiatric disorders marked by social and cognitive deficits, including autism spectrum disorders.
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影响因子：
4.7
作者：
Carasso, BS;Bakshi, VP;Geyer, MA
通讯作者：
Geyer, MA
影响因子：
6.2
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