Cortical microcircuit dysfunction as a result of MET deficiency: a link to autism

描述（由申请人提供）：自闭症谱系障碍（ASD）影响多达1 / 150的儿童。它是一种复杂的发育障碍，以社交缺陷、语言障碍和兴趣限制为特征（Newschaffer et al., 2007; Levitt and Campbell, 2009）。遗传连锁技术最近显示，患有ASD的个体在MET受体酪氨酸激酶（以下简称MET）基因启动子区域发生突变的可能性是常人的三倍，从而导致MET表达减少（campbell et al., 2006; campbell et al., 2007）。MET信号通路对于大脑皮层的正常发育非常重要（Powell et al., 2001; Powell et al., 2003; Levitt et al., 2004; Gutierrez et al., 2004）。干扰这一通路会以多种方式影响皮质发育。然而，皮层回路的功能组织在多大程度上受到MET功能障碍的影响仍是未知的。对ASD研究特别感兴趣的是额叶皮层的突触组织，它涉及行为和执行功能的许多高级认知方面。有证据表明，ASD的皮质区域之间存在长期连接不足（Horwitz等人，198；Courchesne和Pierce, 2005； Kana等人，2007）。从这个角度来看，自闭症谱系障碍是一种皮层回路紊乱。有人提出，在自闭症谱系障碍中也存在过度强化的局部连通性（Courchesne and Pierce, 2005），但这尚未得到直接衡量。MET敲除（MET- ko）小鼠的可用性将使我能够测量由于MET信号通路干扰而导致的突触连通性的变化。我推测，局部突触连接在额叶皮质是过度加强的结果MET- KO。我将通过使用高通量电路映射技术测量皮质纹状体神经元的电路异常来验证这一假设（Weiler等人，2008；Yu等人，2008；Wood等人，2009,Anderson 2010）。我将把重点放在皮质纹状体神经元上，因为这些神经元为其他皮质区域提供远程输入（Wilson, 1987； Reiner等，2003），并且投射是连接额叶皮质与基底神经节和丘脑的回路的关键组成部分，对行为的选择和启动很重要（Albin等，1989）。了解MET-KO中皮层连通性的改变将是表征与ASD相关的皮层回路障碍本质的重要一步。这将为理解自闭症患者大脑变化的机制提供基础。

DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) affects as many as 1 in 150 children. It is a complex developmental disorder characterized by social deficits, language impairment, and restricted interests (Newschaffer et al., 2007; Levitt and Campbell, 2009). Genetic linkage techniques recently revealed that individuals with ASD are three times more likely to have a mutation in the promoter region of the gene for MET receptor tyrosine kinase (hereafter MET), which results in reduced MET expression (Campbel et al., 2006; Campbel et al., 2007). The MET signaling pathway is important for the normal development of the cerebral cortex (Powell et al., 2001; Powell et al., 2003; Levitt et al., 2004; Gutierrez et al., 2004). Interference with this pathway affects cortical development in a number of ways. Still unknown however, is the extent to which the functional organization of cortical circuits is affected by MET dysfunction. Of particular interest to ASD research is the synaptic organization of the frontal cortex, which is involved in many higher order cognitive aspects of behavior and executive functioning. Evidence suggests long-range under-connectivity between cortical areas in ASD (Horwitz et al., 198; Courchesne and Pierce, 2005; Kana et al., 2007). From this view, ASD is a disorder of cortical circuits. It has been proposed that there is also an over-strengthening of local connectivity in ASD (Courchesne and Pierce, 2005), but this has yet to be directly measured. The availability of a MET- knockout (MET-KO) mouse will allow me to measure changes in synaptic connectivity that result from interference with the MET signaling pathway. I hypothesize that local synaptic connections in frontal cortex are over-strengthened as a result of MET- KO. I will test this hypothesis by measuring the circuit abnormalities of corticostriatal neurons with high throughput circuit mapping techniques (Weiler et al., 2008; Yu et al., 2008; Wood et al., 2009, Anderson 2010). I will focus on corticostriatal neurons because these neurons provide long-range input to other cortical areas (Wilson, 1987; Reiner et al., 2003) and the projection is a key component in loops linking the frontal cortex with the basal ganglia and the thalamus important for the selection and initiation of behavior (Albin et al., 1989). Understanding altered cortical connectivity in MET-KO will be an important step towards characterizing the nature of cortical circuit disorders associated with ASD. It will provide a basis for understanding the mechanisms underlying the changes to the brain in ASD. PUBLIC HEALTH RELEVANCE: As many 1 in 150 children are diagnosed with autism spectrum disorder (ASD), which is a complex developmental disorder characterized by abnormal social interactions, language deficits, and restricted interests. Evidence implicates alterations to the circuits of the frontal cortex in ASD, but to date, no detailed, cell-level resolution of synaptic connectivity in non-syndromic ASD has been obtained. We will characterize the cortical circuits of a mouse model of cortical circuit dysfunction in ASD, which will yield important insight into the mechanism underlying differences in the synaptic organization of the frontal cortex, and help understand the changes that occur in the brains of people with ASD.