Autism-like behavioral phenotypes in BTBR T+tf/J mice
Autism-like behavioral phenotypes in BTBR T+tf/J mice
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DOI：
10.1111/j.1601-183x.2007.00330.x
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发表时间：
2008-03-01
影响因子：
2.5
通讯作者：
Crawley, J. N.
中科院分区：
文献类型：
--
作者：
McFarlane, H. G.;Kusek, G. K.;Crawley, J. N.
孤独症是一种病因不明的行为学定义的神经发育障碍。具有核心症状的表面有效性的小鼠模型提供了一种实验方法来测试有关自闭症原因的假设，并提供了评估潜在治疗方法的翻译工具。我们发现，近交系小鼠品系BTBR T+tf/J（BTBR）包含与自闭症的所有三种诊断症状相关的多种行为表型。与C57 BL/6 J（B6）对照组相比，BTBR表现出选择性减少的社会接近，低互惠的社会互动和受损的青少年游戏。BTBR中食物偏好的社会传播受损表明沟通缺陷。重复行为表现为青少年和成年BTBR小鼠的高水平自我梳理。程序能力的综合分析证实，BTBR的社会认知和嗅觉能力是正常的，没有证据表明高度焦虑样特征或运动障碍，支持高度特异性的社会缺陷的解释。BTBR和B6对124个假定自闭症候选基因的数据库比较显示，BTBR遗传背景中存在几个有趣的单核苷酸多态性（SNP），包括Kmo中的非同义编码区多态性。Kmo基因编码犬尿氨酸3-羟化酶，一种调节犬尿烯酸代谢的酶，一种具有神经保护作用的谷氨酸拮抗剂。测序证实了这一编码单核苷酸多态性在Kmo，支持进一步调查这种多态性的自闭症样行为表型的贡献。BTBR近交系的稳健和选择性社交缺陷、重复性自我修饰、遗传稳定性和商业可用性鼓励其作为研究工具来寻找与自闭症病因相关的背景基因，并探索治疗核心症状的疗法。
Autism is a behaviorally defined neurodevelopmental disorder of unknown etiology. Mouse models with face validity to the core symptoms offer an experimental approach to test hypotheses about the causes of autism and translational tools to evaluate potential treatments. We discovered that the inbred mouse strain BTBR T+tf/J (BTBR) incorporates multiple behavioral phenotypes relevant to all three diagnostic symptoms of autism. BTBR displayed selectively reduced social approach, low reciprocal social interactions and impaired juvenile play, as compared with C57BL/6J (B6) controls. Impaired social transmission of food preference in BTBR suggests communication deficits. Repetitive behaviors appeared as high levels of self-grooming by juvenile and adult BTBR mice. Comprehensive analyses of procedural abilities confirmed that social recognition and olfactory abilities were normal in BTBR, with no evidence for high anxiety-like traits or motor impairments, supporting an interpretation of highly specific social deficits. Database comparisons between BTBR and B6 on 124 putative autism candidate genes showed several interesting single nucleotide polymorphisms (SNPs) in the BTBR genetic background, including a nonsynonymous coding region polymorphism in Kmo. The Kmo gene encodes kynurenine 3-hydroxylase, an enzyme-regulating metabolism of kynurenic acid, a glutamate antagonist with neuroprotective actions. Sequencing confirmed this coding SNP in Kmo, supporting further investigation into the contribution of this polymorphism to autism-like behavioral phenotypes. Robust and selective social deficits, repetitive self-grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms.