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150名儿童中的1名。它是一种复杂的发育障碍，以社会缺陷、语言障碍和兴趣受限为特征(Newschaffer等人，2007；Levitt和Campbell，2009)。遗传连锁技术最近显示，ASD患者在MET受体酪氨酸激酶(以下简称MET)基因启动子区发生突变的可能性是后者的三倍，这导致MET表达减少(Campbel等人，2006年；Campbel等人，2007年)。MET信号通路对于大脑皮层的正常发育很重要(Powell等人，2001；Powell等人，2003；Levitt等人，2004；Gutierrez等人，2004)。干扰这一途径会以多种方式影响大脑皮层发育。然而，尚不清楚MET功能障碍对皮质回路功能组织的影响程度。ASD研究特别感兴趣的是额叶皮质的突触组织，它涉及行为和执行功能的许多高级认知方面。证据表明自闭症患者大脑皮层区域之间存在远距离连接不足(Horwitz等人，198；Courchesne和Piells，2005；Kana等人，2007)。从这个角度来看，ASD是一种皮质回路的紊乱。有人提出，ASD的本地连接也存在过度加强(Courchesne和Piels，2005)，但这一点尚未得到直接衡量。MET基因敲除(MET-KO)小鼠的出现将使我能够测量由于干扰MET信号通路而导致的突触连接的变化。我推测，由于MET-KO，额叶皮质的局部突触连接过度增强。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检验这一假设(Weeller等人，2008；Yu等人，2008；Wood等人，2009，Anderson 2010)。我将重点关注皮质纹状体神经元，因为这些神经元向其他皮质区域提供远程输入(Wilson，1987；Reiner等人，2003)，而该投影是连接额叶皮质与基底节和丘脑的环路中的关键组件，对行为的选择和启动至关重要(Albin等人，1989)。了解MET-KO中皮质连接的改变将是确定与ASD相关的皮质回路障碍的性质的重要一步。这将为理解ASD大脑变化的潜在机制提供基础。 公共卫生相关性：每150名儿童中就有1名被诊断出患有自闭症谱系障碍(ASD)，这是一种复杂的发育障碍，特征是不正常的社会互动、语言缺陷和受限的兴趣。有证据表明ASD的额叶皮质回路发生了改变，但迄今为止，在非综合征性ASD中还没有获得详细的、细胞水平的突触连接的分辨率。我们将描述ASD皮层回路功能障碍小鼠模型的皮质回路，这将对揭示额叶皮质突触组织差异的潜在机制提供重要的见解，并有助于理解ASD患者大脑中发生的变化。

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.