自闭症模型大鼠脑区Wnt/β-catenin通路相关基因甲基化修饰及通路活性变化的研究
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摘要
自闭症(autism)是一种广泛性神经发育障碍性疾病,一般于3岁前发病,主要表现出语言交流艰难、社会交往障碍、重复刻板行为三大核心临床症状。此外,autism患者多有个显著头部发育特征,即2-5岁时脑过度增长,大于同龄健康儿童。目前,autism的发病原因尚不清楚,普遍认为是遗传因素和环境因素共同作用的结果,如妊娠早期丙戊酸盐(Valproate, VPA)暴露会大大增加子代罹患autism的风险。
Wnts蛋白是一类参与神经系统发育的重要信号分子,在经典Wnt信号通路中,Wnts蛋白与细胞表面卷曲蛋白受体(Frizzled, Frz)结合而激活下游的散乱蛋白(Dishevelled, Dvl),随后抑制GSK-3β、Axin和APC等分子复合体的形成,从而减少胞浆内β-catenin的降解。β-catenin蓄积并进入细胞核内,与TCF/LEF转录因子结合、诱导相关基因转录,产生一系列生物学效应。据报道,多种神经精神性疾病,如autism、精神分裂和抑郁症等,都可能与Wnt信号通路异常有关。有资料显示wnt2基因的突变与autism的发病有显著的相关性；动物实验表明,敲除了Wnt通路中dvl-1基因的小鼠表现出类似autism的社会行为障碍,也强烈提示Wnt信号通路与autism的发病有关。研究表明,表观遗传机制参与了autism的发病。DNA甲基化修饰是一种重要的表观遗传现象,是后天性的基因修饰过程,是基因对外界环境因素发生应答的重要机制,一般的规律是：甲基化可抑制基因的表达,而去甲基化则可表现出基因活跃表达。在一定的遗传易感性基础上,环境因素通过改变表观遗传信息如基因组甲基化模式而影响特定基因的表达,进而影响脑的发育,导致autism的发生。
那么,autism患者脑内是否存在Wnt信号通路及表观遗传修饰异常?Wnt信号通路活性变化与表观遗传机制异常是否存在联系?目前尚不清楚。针对这这些问题,本课题集中研究autism动物模型及培养神经元中Wnt/β-catenin通路相关基因的甲基化修饰及其与该通路活性变化的关系,以探讨autism发病的相关分子机制。我们主要进行了以下三方面的工作：
一、采用Wistar大鼠,在妊娠第12.5天时,腹腔注射(intraperitoneal injecting, ip) VPA制作子代autism大鼠模型,并运用热板致痛法、倾斜板实验、Morris水迷宫及Nissl染色等方法对模型大鼠进行行为和形态学检测。结果显示,与正常对照组比较,autism模型组大鼠脑发育异常、睁眼时间推迟、方向趋向性机能及伤害性知觉下降、游泳能力差、重复刻板动作增加、学习记忆和空间探索能力差。这些表现与人类autism患者的某些特征极为相似,表明用VPA注射法较成功地制作出了autism大鼠模型。
二、Wnt/β-catenin信号通路相关基因甲基化修饰的研究。运用甲基化特异性PCR (Methylation specific PCR, MSP)和硫转化DNA测序技术(Bisulfite DNA sequencing, BDS)检测VPA模型大鼠额叶皮层和海马脑区及培养神经元Wnt通路信号蛋白Wnt1、Wnt2、WIF-1及DKK1等相关基因启动区的甲基化修饰。MSP结果显示,在VPA模型大鼠额叶皮层和海马脑区及VPA处理培养神经元中,Wnt通路刺激性信号蛋白Wnt1和Wnt2基因启动子区去甲基化水平显著高于对照组(P<0.001),Wnt通路抑制性信号蛋白WIF-1和DKK1基因启动子区去甲基化水平与对照组比较未见显著性差异(P>0.05)。BDS结果显示,wnt1基因启动子区从-723到-328共395bp的片断所含26 CpG双核苷酸中,VPA autism模型组大鼠额叶皮层和海马组织的去甲基化数目显著高于对照组(P< 0.01-0.001); wnt2基因启动子区从-400到-150共250bp的片断所含21 CpG双核苷酸中,VPA autism模型组大鼠额叶皮层和海马组织的去甲基化数目显著高于对照组(P< 0.01), BDS与MSP的结果相一致。Western blot显示,VPA处理对重要表观遗传修饰因子DNMT3b (DNA methyltransferase 3b)的表达无影响。上述结果表明VPA处理具有诱导Wnt/β-catenin信号通路相关基因的去甲基化作用。
三、为揭示Wnt/β-catenin通路相关基因甲基化修饰对该通路活性的影响,应用实时定量PCR, Western blot及免疫荧光染色技术深入研究autism模型大鼠及原代培养神经元Wnt/β-catenin信号通路的活性变化,以及其对神经元生长的作用。实时定量PCR及Western blot结果显示,在VPA模型大鼠额叶皮层和海马脑区及VPA处理培养神经元中,wnt1和wnt2 mRNA及蛋白表达显著高于对照组,并且与VPA剂量呈现正比关系,与启动子区甲基化水平呈现正相关关系(wnt1:R2=0.9621, P< 0.01; wnt2:R2= 0.7805, P<0.05)。免疫荧光组织化学、Western blot及实时定量PCR显示,Wnt/p-catenin通路效应分子β-catenin及其靶基因在VPA自闭模型组及神经元中含量升高,表明Wnt/β-catenin通路活性上调；VPA处理促进神经元生长,表现为突起数目和总长度显著高于对照组；而Wnt/β-catenin通路抑制剂能显著抑制VPA诱导的神经元生长。以上结果表明,Wnt/β-catenin通路相关基因甲基化修饰导致Wnt/β-catenin通路活性上调,VPA促进神经元生长可能由于该通路上调所致。
综上所述,我们的工作提示：环境因素(如VPA暴露)通过表观遗传效应诱导脑组织Wnt/β-catenin通路相关基因甲基化修饰改变,使脑内Wnt信号增强,引起神经元过快生长,患者脑组织体积增加,影响神经元正常发育和联系,阻碍了正常的神经网络形成,从而引起社会交往、情绪和语言等行为方面的异常,最终导致autism的发病。
Autism, a pervasive neurodevelopmental disorders, is belonged to one of autism spetrum diseases (ASDs) and characterized by abnormal social interactions, deficits in the communication and ritualistic-repetitive behaviors. Onsets of the typical clinical symptoms occur in infancy and are fully presented by age 3. Quite a number of autistic patients have a characteristic of brain overgrowth or macrocephaly in 2 to 5-year-old, compared with normal children. The exact etiological factors of autism are still unclear, and both the genetic and environmental are usually proposed to contribute to autism, for example, the prenatal exposure of valproate greatly increases susceptibility to ASDs in the offspring.
Wnts proteins are very important signal molecules in the regulating of neurodevelopment. In the Wnt signaling pathway,β-catenin is generally phosphorylated in GSK-3β, Axin and adenomatous polyposis coli (APC) complex, thus entering the ubiquitin/proteasome degradation pathway. Wnts, together with Frizzled and LRP 5/6 forming a trimeric complex, activates the intracellular disheveled (Dvl). Activated Dvl inhibits GSK-3p and then leads to stabilization, accumulation and further translocation ofβ-catenin into nucleus to activate, together with TCF/LEF, the transcription of the target genes, resulting in series of biological consequences. Previous studies showed that a number of proteins involved in the Wnt signaling pathway demonstrated related phenotypes. The notion of wnt2 as an autism susceptibility gene was supported by screening wnt2 coding sequence for mutations in a large number of autistic probands; the dvl-1 knockout mouse displayed social interaction and sensorimotor gating abnormalities. Therefore, the constellation of Wnt pathway relative genes may contribute to a broad array of psychiatric and behavioral syndromes such as autism, schizophrenia and depressive disorder. It has been proposed that abnormal epigenetic modification is an underlying mechanism in the autism pathogenesis. DNA methylation, an important epigenetic modification, together with other epigenetic and genetic actions determines the levels of gene expression. Generally, methylation makes gene silent, while demethylation activates gene expression. Environmental factors may interact with genetic susceptibility through epigenetic mechanism such as DNA methylation modification to change gene expression to affect the brain development, increasing the likelihood of ASDs.
Whether dysregulation of Wnt/β-catenin pathway and abnormal epigenetic modification coexist in the brain regions of autistic patients? What is the relationship between them? These problems remain still unknown. In this study, we focused on the relationship of the Wnt/β-catenin pathway related genes methylation modifications with the pathway activity in the autistic animal model and primary cultured neurons, hoping to explore the possible pathomechanism of autism. The works had been done as follows:
In the first part of this present study, a kind of autistic animal model was obtained in the offspring of the female Wistar rat that received a single intraperitoneal injection of VPA at the 12.5th pregnancy day, and then the behavioral and morphological tests were performed. The results demonstrated that, compared to the control rats, the autistic ones had abnormal developmental brain, delayed timing of eye opening, lower geotaxis function, pain threshold, lower swimming performance, enhanced ritualistic-repetitive behaviors, lower memorial ability and lower spatial exploratory ability, which were similar to the symptoms in autistic patients. The results from this part showed that the rat model of autism was successfully established.
In the second part, in order to test the methylation modifications of Wnt/β-catenin pathway related genes, methylation specific PCR (MSP) and bisulfite DNA sequencing (BDS) were used to investigate the methylation patterns in the promoter regions of wnt1, wnt2, WIF-1 and DKK1 in the prefrontal cortexes (PFC) and hippocampi (HC) of autistic rats and the primary cultured neurons exposed to VPA. MSP showed partial methylation in the promoter regions in both the VPA-treated and control groups. The changes of demethylation level were detectable specifically in the promoter regions of wntl and wnt2; the demethylation level was significantly higher in the VPA-exposed than the controls (P<0.001). However, no significant changes of demethylation level in the promoter regions of WIF-1 and DKK1 were seen in the VPA-exposed rats, compared with the controls (P> 0.05). Intriguingly, demethylation appeared only in the promoter regions of wntl and wnt2 upregulating canonical Wnt pathway, but not in those of WIF-1 and DKK1 inhibiting canonical Wnt pathway. After MSP assessments, to confirm the changes of wntl and wnt2, we further investigated the methylation status using bisulfite DNA sequencing, which could reveal the details of 26 CpG sites in the 395-bp fragment ranging from-723 to-328 (the transcription start site ATG defined as+1) in the promoter region of wntl as well as of 21 CpG sites in the 250-bp fragment from-400 to-150 in the promoter region of wnt2. From the results consistent with MSP ones, we found that the CpG islands were densely demethylated in both wntl and wnt2 in the prefrontal cortexes and hippocampi of the VPA-exposed rats. The ratio analysis of the unmethylated CpG sites from five independent experiments performed in duplicate indicated that the changed methylation status levels reached statistical significance (P < 0.01-0.001). Western blot showed that VPA had no effects on the protein expression of DNMT3b, an important epigenetic regulating molecule. From the above results, it is demonstrated that VPA induces demethylation modifications in the promoter regions of specific Wnt/β-catenin pathway related genes.
In the third part, in order to study the effects of demethylation modifications on the activity of Wnt/β-catenin pathway, real-time quantitative RT-PCR, western blot and immunoflourescence were used to investigate the activity of Wnt/β-catenin pathway and its effects on neuronal growth. The results from quantitative real-time RT-PCR and western blot detection showed that the mRNA and protein expressions of both wntl and wnt2 were significantly increased in the PFC and HC of autistic rats and the VPA-exposed cultured neurons, compared to the controls. Furthermore, the mRNA and protein expression levels of both wntl and wnt2 were dose-dependent and directly correlated with the relative demethylation level in the promoter region (wntl: R2= 0.9621, P< 0.01; wnt2:R2= 0.7805, P< 0.05).β-Catenin, the key intracellular molecular effector, and the targeted genes of Wnt/β-catenin pathway were also enhanced in the autistic rats and the VPA-exposed cultured neurons, symbolizing the upregulation of Wnt/β-catenin pathway activity. VPA promoted the neurite morphological complexity, manifesting as significant increment of number of neurite branches and total neurite length in comparison with the controls. The promotion of neurite complexity induced by VPA could be suppressed by the inhibitor of Wnt/β-catenin pathway. These results demonstrated that VPA induced the upregulation of Wnt/β-catenin pathway through DNA demethylation on specific genes, and further promote the neuronal growth.
In conclusion, we demonstrated that enviromental factors such as VPA induced methylation modifications on the specific genes of Wnt/β-catenin pathway and concomitant overexpressions of both mRNA and protein, thus resulting in the upregulation of Wnt/β-catenin pathway. The upregulation of Wnt/β-catenin pathway promotes neuronal growth and enlarge the brain, which affect the neuronal development and connections, resulting in behavioral, emotional and linguistical abnormality and ending with autism. Our study suggests an epigenetic action via which enviromental factors, when exposed in early pregnancy, could induce dysregulation of signaling pathway, further facilitating susceptibility to ASDs.
Wnts蛋白是一类参与神经系统发育的重要信号分子,在经典Wnt信号通路中,Wnts蛋白与细胞表面卷曲蛋白受体(Frizzled, Frz)结合而激活下游的散乱蛋白(Dishevelled, Dvl),随后抑制GSK-3β、Axin和APC等分子复合体的形成,从而减少胞浆内β-catenin的降解。β-catenin蓄积并进入细胞核内,与TCF/LEF转录因子结合、诱导相关基因转录,产生一系列生物学效应。据报道,多种神经精神性疾病,如autism、精神分裂和抑郁症等,都可能与Wnt信号通路异常有关。有资料显示wnt2基因的突变与autism的发病有显著的相关性；动物实验表明,敲除了Wnt通路中dvl-1基因的小鼠表现出类似autism的社会行为障碍,也强烈提示Wnt信号通路与autism的发病有关。研究表明,表观遗传机制参与了autism的发病。DNA甲基化修饰是一种重要的表观遗传现象,是后天性的基因修饰过程,是基因对外界环境因素发生应答的重要机制,一般的规律是：甲基化可抑制基因的表达,而去甲基化则可表现出基因活跃表达。在一定的遗传易感性基础上,环境因素通过改变表观遗传信息如基因组甲基化模式而影响特定基因的表达,进而影响脑的发育,导致autism的发生。
那么,autism患者脑内是否存在Wnt信号通路及表观遗传修饰异常?Wnt信号通路活性变化与表观遗传机制异常是否存在联系?目前尚不清楚。针对这这些问题,本课题集中研究autism动物模型及培养神经元中Wnt/β-catenin通路相关基因的甲基化修饰及其与该通路活性变化的关系,以探讨autism发病的相关分子机制。我们主要进行了以下三方面的工作：
一、采用Wistar大鼠,在妊娠第12.5天时,腹腔注射(intraperitoneal injecting, ip) VPA制作子代autism大鼠模型,并运用热板致痛法、倾斜板实验、Morris水迷宫及Nissl染色等方法对模型大鼠进行行为和形态学检测。结果显示,与正常对照组比较,autism模型组大鼠脑发育异常、睁眼时间推迟、方向趋向性机能及伤害性知觉下降、游泳能力差、重复刻板动作增加、学习记忆和空间探索能力差。这些表现与人类autism患者的某些特征极为相似,表明用VPA注射法较成功地制作出了autism大鼠模型。
二、Wnt/β-catenin信号通路相关基因甲基化修饰的研究。运用甲基化特异性PCR (Methylation specific PCR, MSP)和硫转化DNA测序技术(Bisulfite DNA sequencing, BDS)检测VPA模型大鼠额叶皮层和海马脑区及培养神经元Wnt通路信号蛋白Wnt1、Wnt2、WIF-1及DKK1等相关基因启动区的甲基化修饰。MSP结果显示,在VPA模型大鼠额叶皮层和海马脑区及VPA处理培养神经元中,Wnt通路刺激性信号蛋白Wnt1和Wnt2基因启动子区去甲基化水平显著高于对照组(P<0.001),Wnt通路抑制性信号蛋白WIF-1和DKK1基因启动子区去甲基化水平与对照组比较未见显著性差异(P>0.05)。BDS结果显示,wnt1基因启动子区从-723到-328共395bp的片断所含26 CpG双核苷酸中,VPA autism模型组大鼠额叶皮层和海马组织的去甲基化数目显著高于对照组(P< 0.01-0.001); wnt2基因启动子区从-400到-150共250bp的片断所含21 CpG双核苷酸中,VPA autism模型组大鼠额叶皮层和海马组织的去甲基化数目显著高于对照组(P< 0.01), BDS与MSP的结果相一致。Western blot显示,VPA处理对重要表观遗传修饰因子DNMT3b (DNA methyltransferase 3b)的表达无影响。上述结果表明VPA处理具有诱导Wnt/β-catenin信号通路相关基因的去甲基化作用。
三、为揭示Wnt/β-catenin通路相关基因甲基化修饰对该通路活性的影响,应用实时定量PCR, Western blot及免疫荧光染色技术深入研究autism模型大鼠及原代培养神经元Wnt/β-catenin信号通路的活性变化,以及其对神经元生长的作用。实时定量PCR及Western blot结果显示,在VPA模型大鼠额叶皮层和海马脑区及VPA处理培养神经元中,wnt1和wnt2 mRNA及蛋白表达显著高于对照组,并且与VPA剂量呈现正比关系,与启动子区甲基化水平呈现正相关关系(wnt1:R2=0.9621, P< 0.01; wnt2:R2= 0.7805, P<0.05)。免疫荧光组织化学、Western blot及实时定量PCR显示,Wnt/p-catenin通路效应分子β-catenin及其靶基因在VPA自闭模型组及神经元中含量升高,表明Wnt/β-catenin通路活性上调；VPA处理促进神经元生长,表现为突起数目和总长度显著高于对照组；而Wnt/β-catenin通路抑制剂能显著抑制VPA诱导的神经元生长。以上结果表明,Wnt/β-catenin通路相关基因甲基化修饰导致Wnt/β-catenin通路活性上调,VPA促进神经元生长可能由于该通路上调所致。
综上所述,我们的工作提示：环境因素(如VPA暴露)通过表观遗传效应诱导脑组织Wnt/β-catenin通路相关基因甲基化修饰改变,使脑内Wnt信号增强,引起神经元过快生长,患者脑组织体积增加,影响神经元正常发育和联系,阻碍了正常的神经网络形成,从而引起社会交往、情绪和语言等行为方面的异常,最终导致autism的发病。
Autism, a pervasive neurodevelopmental disorders, is belonged to one of autism spetrum diseases (ASDs) and characterized by abnormal social interactions, deficits in the communication and ritualistic-repetitive behaviors. Onsets of the typical clinical symptoms occur in infancy and are fully presented by age 3. Quite a number of autistic patients have a characteristic of brain overgrowth or macrocephaly in 2 to 5-year-old, compared with normal children. The exact etiological factors of autism are still unclear, and both the genetic and environmental are usually proposed to contribute to autism, for example, the prenatal exposure of valproate greatly increases susceptibility to ASDs in the offspring.
Wnts proteins are very important signal molecules in the regulating of neurodevelopment. In the Wnt signaling pathway,β-catenin is generally phosphorylated in GSK-3β, Axin and adenomatous polyposis coli (APC) complex, thus entering the ubiquitin/proteasome degradation pathway. Wnts, together with Frizzled and LRP 5/6 forming a trimeric complex, activates the intracellular disheveled (Dvl). Activated Dvl inhibits GSK-3p and then leads to stabilization, accumulation and further translocation ofβ-catenin into nucleus to activate, together with TCF/LEF, the transcription of the target genes, resulting in series of biological consequences. Previous studies showed that a number of proteins involved in the Wnt signaling pathway demonstrated related phenotypes. The notion of wnt2 as an autism susceptibility gene was supported by screening wnt2 coding sequence for mutations in a large number of autistic probands; the dvl-1 knockout mouse displayed social interaction and sensorimotor gating abnormalities. Therefore, the constellation of Wnt pathway relative genes may contribute to a broad array of psychiatric and behavioral syndromes such as autism, schizophrenia and depressive disorder. It has been proposed that abnormal epigenetic modification is an underlying mechanism in the autism pathogenesis. DNA methylation, an important epigenetic modification, together with other epigenetic and genetic actions determines the levels of gene expression. Generally, methylation makes gene silent, while demethylation activates gene expression. Environmental factors may interact with genetic susceptibility through epigenetic mechanism such as DNA methylation modification to change gene expression to affect the brain development, increasing the likelihood of ASDs.
Whether dysregulation of Wnt/β-catenin pathway and abnormal epigenetic modification coexist in the brain regions of autistic patients? What is the relationship between them? These problems remain still unknown. In this study, we focused on the relationship of the Wnt/β-catenin pathway related genes methylation modifications with the pathway activity in the autistic animal model and primary cultured neurons, hoping to explore the possible pathomechanism of autism. The works had been done as follows:
In the first part of this present study, a kind of autistic animal model was obtained in the offspring of the female Wistar rat that received a single intraperitoneal injection of VPA at the 12.5th pregnancy day, and then the behavioral and morphological tests were performed. The results demonstrated that, compared to the control rats, the autistic ones had abnormal developmental brain, delayed timing of eye opening, lower geotaxis function, pain threshold, lower swimming performance, enhanced ritualistic-repetitive behaviors, lower memorial ability and lower spatial exploratory ability, which were similar to the symptoms in autistic patients. The results from this part showed that the rat model of autism was successfully established.
In the second part, in order to test the methylation modifications of Wnt/β-catenin pathway related genes, methylation specific PCR (MSP) and bisulfite DNA sequencing (BDS) were used to investigate the methylation patterns in the promoter regions of wnt1, wnt2, WIF-1 and DKK1 in the prefrontal cortexes (PFC) and hippocampi (HC) of autistic rats and the primary cultured neurons exposed to VPA. MSP showed partial methylation in the promoter regions in both the VPA-treated and control groups. The changes of demethylation level were detectable specifically in the promoter regions of wntl and wnt2; the demethylation level was significantly higher in the VPA-exposed than the controls (P<0.001). However, no significant changes of demethylation level in the promoter regions of WIF-1 and DKK1 were seen in the VPA-exposed rats, compared with the controls (P> 0.05). Intriguingly, demethylation appeared only in the promoter regions of wntl and wnt2 upregulating canonical Wnt pathway, but not in those of WIF-1 and DKK1 inhibiting canonical Wnt pathway. After MSP assessments, to confirm the changes of wntl and wnt2, we further investigated the methylation status using bisulfite DNA sequencing, which could reveal the details of 26 CpG sites in the 395-bp fragment ranging from-723 to-328 (the transcription start site ATG defined as+1) in the promoter region of wntl as well as of 21 CpG sites in the 250-bp fragment from-400 to-150 in the promoter region of wnt2. From the results consistent with MSP ones, we found that the CpG islands were densely demethylated in both wntl and wnt2 in the prefrontal cortexes and hippocampi of the VPA-exposed rats. The ratio analysis of the unmethylated CpG sites from five independent experiments performed in duplicate indicated that the changed methylation status levels reached statistical significance (P < 0.01-0.001). Western blot showed that VPA had no effects on the protein expression of DNMT3b, an important epigenetic regulating molecule. From the above results, it is demonstrated that VPA induces demethylation modifications in the promoter regions of specific Wnt/β-catenin pathway related genes.
In the third part, in order to study the effects of demethylation modifications on the activity of Wnt/β-catenin pathway, real-time quantitative RT-PCR, western blot and immunoflourescence were used to investigate the activity of Wnt/β-catenin pathway and its effects on neuronal growth. The results from quantitative real-time RT-PCR and western blot detection showed that the mRNA and protein expressions of both wntl and wnt2 were significantly increased in the PFC and HC of autistic rats and the VPA-exposed cultured neurons, compared to the controls. Furthermore, the mRNA and protein expression levels of both wntl and wnt2 were dose-dependent and directly correlated with the relative demethylation level in the promoter region (wntl: R2= 0.9621, P< 0.01; wnt2:R2= 0.7805, P< 0.05).β-Catenin, the key intracellular molecular effector, and the targeted genes of Wnt/β-catenin pathway were also enhanced in the autistic rats and the VPA-exposed cultured neurons, symbolizing the upregulation of Wnt/β-catenin pathway activity. VPA promoted the neurite morphological complexity, manifesting as significant increment of number of neurite branches and total neurite length in comparison with the controls. The promotion of neurite complexity induced by VPA could be suppressed by the inhibitor of Wnt/β-catenin pathway. These results demonstrated that VPA induced the upregulation of Wnt/β-catenin pathway through DNA demethylation on specific genes, and further promote the neuronal growth.
In conclusion, we demonstrated that enviromental factors such as VPA induced methylation modifications on the specific genes of Wnt/β-catenin pathway and concomitant overexpressions of both mRNA and protein, thus resulting in the upregulation of Wnt/β-catenin pathway. The upregulation of Wnt/β-catenin pathway promotes neuronal growth and enlarge the brain, which affect the neuronal development and connections, resulting in behavioral, emotional and linguistical abnormality and ending with autism. Our study suggests an epigenetic action via which enviromental factors, when exposed in early pregnancy, could induce dysregulation of signaling pathway, further facilitating susceptibility to ASDs.
引文
[1]DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E, Dager SR, Schmitz C, Schultz RT, Crawley J, Young LJ. The developmental neurobiology of autism spectrum disorder [J]. J Neurosci,2006,26 (26):6897-6906.
[2]张建娜.儿童孤独症的诊断与治疗现状[J].中国医刊,2005,40(4)：5-8.
[3]Muhle R, Trentacoste SV, Rapin I. The genetics of autism [J]. Pediatrics,2004,113 (5):e472-486.
[4]Dawson G, Webb S, Schellenberg G, Dager S, Friedman S, Aylward E, Richards T. Defining the broader phenotype of autism:genetics, brain, and behavioral perspectives [J]. Dev Psychopathol,2002,14 (3):581-611.
[5]Miller MT, Stromland K, Ventura L, Johansson M, Bandim JM, Gillberg C. Autism associated with conditions characterized by developmental errors in early embryogenesis:a mini review [J] Int J Dev Neurosci,2005,23 (2-3):201-219.
[6]Gutknecht L. Full-genome scans with autistic disorder [J]. Behavior genetics,2001, 31(1):113-123.
[7]Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E, Coleman M, Zappella M, Aschauer H, Van Maldergem L, Penet C, Feingold J, Brice A, Leboyer M. Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study [J]. Hum Mol Genet,1999,8 (5): 805-812.
[8]Freitag CM. The genetics of autistic disorders and its clinical relevance:a review of the literatur [J]. Mol Psychiatry,2007,12 (1):2-22.
[9]Wilkerson DS. Volpe AG, Dean RS, et al. Perinatal complications as predictors of infantile autism [J]. Int J Neurosci,2002,112 (9):1085-1098.
[10]Hultman CM, Sparen P. Cnattingus S. Perinatal risk factors for infantile autism [J]. Epidemiology,2002,13 (4):417-423.
[11]Reichelt KL, Hole K, Hamberger A, Saelid G, Edminson PD, Braestrup CB, Lingjaerde O, Ledaal P, H. O. Biologically active peptide-containing fractions in schizophrenia and childhood autism [J]. Adv Biochem Psychopharmacol,1981, 28:627-643.
[12]Ingram JL, Peckham SL, Tisdale B, P.M. R. Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism [J]. Neurotoxicol teratol,2000,22 (3):319-324.
[13]Schneider T, Przewlocki R. Behavioral alterations in rats prenatally exposed to valproic acid:Animal model of autism [J]. Neuropsychopharmacology,2005,30 (1):80-89.
[14]Wagner GC, Reuhl KR, Cheh M, McRae P, Halladay AK. A new neurobehavioral model of autism in mice:Pre-and postnatal exposure to sodium valproate [J]. J Autism Dev Disord,2006,36 (6):779-793.
[15]Christianson AL, Chesler N, Kromberg JG. Fetal valproate syndrome:clinical and neuro-developmental features in two sibling pairs [J]. Dev Med Child Neurol, 1994,36 (4):361-369.
[16]Ornoy A. Valproic acid in pregnancy:how much are we endangering the embryo and fetus? [J]. Reprod Toxicol,2009,28 (1):1-10.
[17]Hallene KL, Oby E, Lee BJ, Santaguida S, Bassanini S, Cipolla M, Marchi N, Hossain M, Battaglia G, Janigro D. Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations [J]. Neuroscience,2006,142 (1): 267-283.
[18]Schumacher HJ, Terapane J, Jordan RL, Wilson JG. The teratogenic activity of a thalidomide analogue, EM 12 in rabbits, rats, and monkeys [J]. Teratology,1972, 5 (2):233-240.
[19]Stromland K, Nordin V, Miller M, Akerstrom B, Gillberg C. Autism in thalidomide embryopathy:a population study [J]. Dev Med Child Neurol,1994,36 (4): 351-356.
[20]Padhye U. Excess dietary iron is the root cause for increase in childhood autism and allergies [J]. Med Hypotheses,2003,61 (1):220-222.
[21]Halsey NA, Hyman SL. Measles-mumps-rubella vaccine and autistic spectrum disorder:report from the new challenges in childhood immunizations conference convener oak brook [J]. Illinoi Pediatrics,2001,107 (1):E84.
[22]Stanfield AC, McIntosh AM, Spencer MD, Philip R, Gaur S, Lawrie SM. Towards a neuroanatomy of autism:A systematic review and meta-analysis of structural magnetic resonance imaging studies [J]. Eur Psychiatry,2008,23 (4):1-11.
[23]Palmen SJ, Engeland H, Hof PR. Neuropathogical findings in autism [J]. Brain, 2004,127 (12):2572-2583.
[24]Minshew NJ, Williams DL. The new neurobiology of autism [J]. Arch neurol, 2007,64 (7):945-950.
[25]Palmen SJMC, van Engeland H, Hof PR, Schmitz C. Neuropathological findings in autism [J]. Brain,2004,127 (Pt 12):2572-2583.
[26]Dean C, Dresbach T. Neuroligins and neurexins:linking cell adhesion, synapse formation and cognitive function [J]. Trends Neurosci,2006,29 (1):21-29.
[27]Polleux F, Lauder JM. Toward a developmental neurobiology of autism [J]. Ment Retard Dev Disabil Res Rev,2004,10 (4):303-317.
[28]Nelson WJ, Nusse R. Convergence of Wnt, P-Catenin, and Cadherin Pathways [J]. Science,2004,303 (5663):1483-1487.
[29]McEntee MF, Chiu CH, Whelan J. Relationship of β-catenin and Bcl-2 expression to sulindac-induced regression of intestinal tumors in Min mice [J]. Carcinogenesis,1999,20 (4):635-640.
[30]Davies NM, Watson MS. Clinical pharmacokinetics of sulindac:A dynamic old drug [J]. Clin Pharmacokinet,1997,32 (6):437-459.
[31]Rice PL, Kelloff J, Sullivan H, Driggers LJ, Beard KS, Kuwada S, Piazza G, Ahnen DJ. Sulindac metabolites induce caspase-and proteasome-dependent degradation of catenin protein in human colon cancer cells [J]. Mol Cancer Ther, 2003,2 (9):885-892.
[32]Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J, Braun T, Beck G, Folstein SE, Haines JL, Sheffield VC. Evidence supporting WNT2 as an autism susceptibility gene [J]. Am J Med Genet,2001,105 (5):406-413.
[33]Lijam N, Paylor R, McDonald MP, Crawley JN, Deng CX, Herrup K, Stevens KE, Maccaferri G, McBain CJ, Sussman DJ, WynshawBoris A. Social interaction and sensorimotor gating abnormalities in mice lacking Dvll [J]. Cell,1997,90 (5): 895-905.
[34]陈明军,于剑锋,柴继侠,徐理,王中平,李瑞锡,彭裕文.Wnt通路信号蛋白β-catenin和GSK-3 β在孤独症模型大鼠脑中表达的变化[J].神经解剖学杂志,2009,25(4)：361-368.
[35]Lawler CP, Croen LA, Grether JK. Identifying environmental contributions to autism:provocative clues and false leads [J]. Ment Retard Dev Disabil Res Rev, 2004,10 (2):292-302.
[36]Vliet J, Oates NA, Law W. Epigenetic mechanisms in the context of complex diseases [J]. Cellular and molecular life sciences,2007,64 (4):1531-1538.
[37]Schanen NC. Epigenetics of autism spectrum disorders [J]. Hum Mol Genet,2006, 15 R138-R150.
[38]Tchurikov NA. Molecular mechanisms of epigenetics [J]. Biochemistry (Mosc), 2005,70 (4):406-423.
[39]Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, aydon C, Ropero S, Petrie K. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer [J]. Nat Genet,2005,37 (2):391-400.
[40]Frigola J, Song J, Stirzaker C, Hinshelwood RA, Peinado MA, Clark SJ. Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band [J]. Nat Genet,2006,38 (2):540-549.
[41]Ting AH, Schuebel KE, Herman JG, Baylin S. Short double-stranded RNA induces transcriptional gene silencing in human cancer cells in the absence of DNA methylation [J]. Nat Genet,2005,37 (3):906-910.
[42]Wolffe AP, Jones PL, Wade PA. DNA methylation [J]. PNAS,1999,96 (11): 5894-5896.
[43]Okano M, Bell DW, D.A. H. DNA methyltransferases DNMT3a and DNMT3b are essential for de novo methylation and mammalian development [J]. Cell,1999,99 (1):247-257.
[44]Fuks F. DNA methylation and histone modifications:teaming up to silence genes [J]. Curr Opin Genet Dev,2005,15 (2):191-199.
[45]Levenson JM, Roth TL, Lubin FD, Miller CA, Huang IC, Desai P, Malone LM, J.D. S. Evidence that DNA (Cytosine-5) methyltrans-ferase regulates synaptic plasticity in the hippocampus [J]. J Biol Chem,2006,281 (23):15763-15773.
[46]Santos F, Dean W. Epigenetic reprogramming during early development in mammals [J] Reproduction,2004,127 (2):643-651.
[47]Samaco RC, Hogart A, LaSalle JM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders:MECP2 deficiency causes reduced expression of UBE3A and GABRB3 [J]. Hum Mol Genet,2005,14 (2):483-492.
[48]Thatcher KN, Peddada S, Yasui DH, Lasalle JM. Homologous pairing of 15q11-13 imprinted domains in brain is developmentally regulated but deficient in Rett and autism samples [J]. Hum Mol Genet,2005,14 (3):785-797.
[49]Rice D, Barone SJ. Critical periods of vulnerability for the developing nervous system:evidence from humans and animal models [J]. Environ Health Perspect, 2000,108 (Suppl 3):511-533.
[50]Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH. Fetal valproate syndrome and autism:additional evidence of an association [J]. Dev Med Child Neurol,2001,43 (3):202-206.
[51]Miyazaki K, Narita N, Narita M. Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring:implication for pathogenesis of autism [J]. Int J Dev Neurosci,2005,23 (2-3):287-297.
[52]Arndt TL, Stodgell CJ, Rodier PM. The teratology of autism [J]. Int J Dev Neurosci,2005,23 (2-3):189-199.
[53]Tunnicliff G. Actions of sodium valproate on the central nervous system [J]. J Physiol Pharmacol,1999,50 (3):347-365.
[54]Rasalam AD, Hailey H, Williams JHG, Moore SJ, Turnpenny PD, Lloyd DJ, Dean JCS. Characteristics of fetal anticonvulsant syndrome associated autistic disorder [J]. Dev Med Child Neurol,2005,47 (8):551-555.
[55]Wegner C, Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis:implication for mechanism of teratogenesis [J]. Neurology, 1992,42 (Suppl.5):17-24.
[56]Bachevalier J, Loveland KA. The orbitofrontal-amygdala circuit and self-regulation of social-emotional behavior in autism [J]. Neuroscience and Biobehavioral Reviews,2006,30 (1):97-117.
[57]Katherine AL, Jocelyne B, Deborah A. Fronto-limbic Functioning in Children and Adolescents With and Without Autism [J]. Neuropsychologia,2008,46 (1): 49-62.
[58]Amaral DG, Schumann CM, Nordahl CW Neuroanatomy of autism [J]. Trends Neurosci,2008,31 (3):137-145.
[59]Nanson JL. Autism in fetal alcohol syndrome:a report of six cases [J]. Alcohol Clin Exp Res,1992,16 (2):558-565.
[60]Nelson KB, Bauman ML. Thimerosal and autism? [J]. Pediatrics,2003,12 (3): 674-679.
[61]Tazumi T, Hori E, Uwano T, Umeno K, Tanebe K, Tabuchi E, Ono T, Nishijo H. Effects of prenatal maternal stress by repeated cold environment on behavioral and emotional development in the rat offspring [J]. Behav Brain Res,2005,162 (1):153-160.
[62]王维霞,王月华,陈明军,上野照子,小野武年,西条寿夫,李瑞锡,彭裕文.PV阳性神经元在孤独症模型大鼠情绪与认知相关脑区内的表达[J].神经解剖学杂志,2008,24(2)：131-140.
[63]Carper RA, Moses P, Tigue ZD, Courchesne E. Cerebral lobes in autism:Early hyperplasia and abnormal age effects [J]. Neuroimage,2002,16 (4):1038-1051.
[64]Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism [J]. JAMA,2003,290 (3):337-344.
[65]Courchesne E, Pierce K. Brain overgrowth in autism during a critical time in development:implications for frontal pyramidal neuron and interneuron development and connectivity [J]. Int J Dev Neurosci,2005,23 (2-3):153-170.
[66]Belmonte MK, Cook EH, Anderson GM. Autism as a disorder of neural information processing:Directions for research and targets for therapy [J]. Mol Psychiatry,2004,9 (2):646-663.
[67]Sadamatsu M, Kanai H, Xu X, Liu Y, Kato N. Review of animal models for autism: implication of thyroid hormone [J]. Congenit Anom (Kyoto),2006,46 (1):1-9.
[68]Courchesne E, Karns C, H. D. Unusual brain growth patterns in early life in patients with autistic disorder [J]. Neurology,2001,57 (1):245-254.
[69]Lee M, Martin-Ruiz C, Graham A. Nicotinic receptor abnormalities in the cerebellar cortex in autism [J]. Brain,2002,125 (4):1483-1495.
[70]Allen G, Courchesne E. Differential effects of developmental cerebellar abnormality on cognitive and motor functions in the cerebellum:An fMRI study of autism [J]. Am J Psychiatry,2003,160 (1):262-273.
[71]Kates WR, Burnette CP, Eliez S. Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism [J]. Am J Psychiatry,2004, 161 (2):539-546.
[72]Courchesne E. Brain development in autism:early overgrowth followed by premature arrest of growth [J]. Ment Retard Dev Disabil Res Rev,2004,10 (2): 106-111.
[73]Dahl C, Guldberg P. DNA methylation analysis techniques [J]. Biogerontology, 2003,4 (4):233-250.
[74]Hagerman RJ, Ono MY, Hagerman PJ. Recent advances in fragile X:a model for autism and neurodegeneration [J]. Curr Opin Psychiatry,2005,18 (2):490-496.
[75]Fukuchi M, Nii T, Ishimaru N, Minamino A, Hara D, Takasaki I, Tabuchi A, Tsuda M. Valproic acid induces up-or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions [J]. Neuroscience Research,2009,65 (1):35-43.
[76]Milutinovic S, D'Alessio AC, Detich N, Szyf M. Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes [J]. Carcinogenesis,2007,28 (3):560-571.
[77]Detich N, Bovenzi V, Szyf M. Valproate induces replication-independent active DNA demethylation [J]. J Biol Chem,2003,278 (30):27586-27592.
[78]Panhuysen M, Vogt WDM, Blanquet V, Brodski C, Heinzmann U, Beisker W, Wurst W. Effects of Wnt1 signaling on proliferation in the developing mid-/hindbrain region [J]. Mol Cell Neurosci,2004,26 (1):101-111.
[79]Ciani L, Salinas PC. WNTs in the vertebrate nervous system:from patterning to neuronal connectivity [J]. Nat Rev Neurosci,2005,6 (5):351-362.
[80]De Ferrari GV, Moon RT. The ups and downs of Wnt signaling in prevalent neurological disorders [J]. Oncogene,2006,25 (57):7545-7553.
[81]Chenn A, Walsh CA. Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta-catenin overexpressing transgenic mice [J]. Cereb Cortex,2003,13 (6):599-606.
[82]Brault V, Moore R, Kutsch S, Ishibashi M, Rowitch DH, McMahon AP, Sommer L, Boussadia O, Kemler R. Inactivation of the beta-catenin gene by Wntl-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development [J]. Development,2001,128 (8):1253-1264.
[83]Guilland JC, Favier A, Potier de Courcy G, Galan P, Hercberg S. Hyper-homocysteinemia:An independent risk factor or a simple marker of vascular disease? [J]. Pathol Biol,2003,51:101-110.
[84]Lee ME, Wang H. Homocysteine and hypomethylation. A novel link to vascular disease [J]. Trends Cardiovasc Med,1999,9:49-54.
[85]Clarke S. Protein methylation [J]. Curr Opin Cell Biol,1993,5:977-983.
[86]Yerby MS. Management issues for women with epilepsy. Neural tube defects and folic acid supplementation [J]. Neurology,2003,61 (6 Suppl 2):S23-26.
[87]Wegner C, Nau H. Diurnal variation of folate concentrations in mouse embryo and plasma:the protective effect of folinic acid on valproic acid induced teratogenicity is time dependent [J]. Reprod Toxicol,1991,5 (6):465-471.
[88]Courchesne E, Pierce K, Schumann CM, Redcay E, Buckwalter JA, Kennedy DP, Morgan J. Mapping Early Brain Development in Autism [J]. Neuron,2007,56 399-413.
[89]Hazlett HC, Poe M, Gerig G, Smith RG, Provenzale J, Ross A, Gilmore J, Piven J. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years [J]. Arch Gen Psychiatry,2005,62:1366-1376.
[90]Ritvo ER, Freeman BJ, Scheibel AB, Duong T, Robinson H, Guthrie D. Lower Purkinje cell counts in the cerebella of four autistic subjects:initial findings of the UCLA-NSAC autopsy research report [J]. Am J Psychiatry,1986,143:862-876.
[91]Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism. In: Bauman ML, Kemper TL, editors. The neurobiology of autism [M]. Baltimore: Johns Hopkins University Press,1994:119-145.
[92]Buxbaum JD, Cai G, Chaste P. Mutation screening of the PTEN gene in patients with autism spectrum disordem and maclrocephaly [J]. Am J Med Genet B (Neuropsychiatr Genet),2007,144:484-491.
[93]Campos VE, Du M, Li Y. Increased seizure susceptibility and cortical malformation in β-catenin mutant mice [J]. Biochem Biophys Res Commun,2004, 320 (2):606-614.
[94]Endo Y, Rubin JS. Wnt signaling and neurite outgrowth:insights and questions. Cancer Sci,2007,98 (9):1311-1317.
[95]Cotter D, Kerwin R, al-Sarraji S, Brion JP, Chadwich A, Lovestone S. Abnormalities of Wnt signalling in schizophrenia-evidence for neurodevelopmental abnormality [J]. NeuroRep,1998,9 1379-1383.
[96]Hall AC, Lucas FR, Salinas PC. Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling [J]. Cell,2000,100 (5): 525-535.
[97]Patapoutian A, Reichardt LF. Roles of Wnt proteins in neural development and maintenance [J]. Curr Opin Neurobiol,2000,10 (3):392-399.
[98]Asghari V, Wang JF, Reiach JS, Young LT. Differential effects of mood stabilizers on Fos/Jun proteins and AP-1 DNA binding activity in human neuroblastoma SH-SY5Y cells [J]. Mol Brain Res,1998,58 (1-2):95-102.
[99]Prithviraj R, Kelly KM, Espinoza-Lewis R, Hexom T, Clark AB, Inglis FM. Differential regulation of dendrite complexity by AMPA receptor subunits GluR1 and GluR2 in motor neurons [J]. Dev Neurobiol,2008,68 (2):247-264.
[100]Frackowiak J, Cohen IL, Jenkins E, Flory M, Mazur-Kolecka B. Formation of neuronal processes in a cell culture model of neuronal differentiation in autism [J]. Int J Dev Neurosci,2006,24 (8):533-533.
[101]Koornstra JJ, Rijcken FEM, Oldenhuis CNAM, Zwart N, van der Sluis T, Hollema H, De Vries EGE, Keller JJ, Offerhaus JA, Giardiello FM, Kleibeuker JH. Sulindac inhibits β-catenin expression in normal-appearing colon of hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis patients [J]. Cancer Epidemiol Biomarkers Prev,2005,14 (7):1608-1612.
[102]Boon EMJ, Keller JJ, Wormhoudt TAM, Giardiello2 FM, Offerhaus1 GJA, van der Neut R, Pals ST. Sulindac targets nuclear Offerhaus-catenin accumulation and Wnt signaling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines [J]. Br J Cancer,2004,90 (1):224-229.
[1]DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E, Dager S, Schmitz C, Schultz R, Crawley J, Young L. The developmental neurobiology of autism spectrum disorder [J]. J Neurosci,2006,26(26):6897-6906.
[2]Ballaban-Gil K, Tuchman R. Epilepsy and epileptiform EEG:Association with autism and language disorders [J]. Ment Retard Dev Disabil Res Rev,2000,6: 300-308.
[3]张建娜.儿童孤独症的诊断与治疗现状[J].中国医刊,2005,40(4)：5-8.
[4]Webbs D, Schellenbery G. Defining the broader phenotype of autism:genetics, brain, and behavioral perspectives [J]. Dev Psychopathol,2002,14(9):581-611.
[5]Bailey A, Le Couteur A, Gottesman I. Autism as a strongly genetic disorder: evidence from a British twin study [J]. Psychol Med,1995,25:63-77.
[6]Jorde L, Hassted S, Ritvo E. Complex segregation analysis of autism [J]. Am J Hum Genet,1991,49:932-938.
[7]Rutter M. Genetic Studies of Autism:From the 1970s into the Millennium [J]. J Abnormal Child Paychol,2000,28:3-14.
[8]Gutknecht L. Full-genome scans with autistic disorder [J]. Behavior genetics, 2001,31(1):113-123.
[9]Philippe A. Paris autism research International sibpair study:genome-wide scan for autism susceptibility genes [J]. Hum mol geneti,1999,8(1):805-812.
[10]Freitag C. The genetics of autistic disorders and its clinical relevance:a review of the literatur [J]. Mol psychiatry,2007,12(1):1-22.
[11]Rubenstein J, Merzenich M. Model of autism:increased ratio of excitation/inhibition in key neural systems [J]. Genes, Brain and Behavior,2003, 2:255-267.
[12]Buxbaum J, Silverman J, Smith C. Association between a GABARB3 polymorphism and autism [J]. Mol psychiatry,2002,7:311-316.
[13]Meldrum B. Glutamate as a neurotransmitter in the brain:review of physiology and pathology [J].J Nutr,2000,130:s1007-s1015.
[14]Jamain S, Betancur C, Quach H. Linkage and association of the glutamate receptor 6 gene with autism [J]. Mol Psychiatry,2002,7:217-220.
[15]Leboyer M, Philippe A, Bouvard M. Whole blood serotonin and plasma beta-endourphin in autistic probands and their first-degree relatives [J]. Biol psychiatry,1999,45(2):158-163.
[16]Cook E, Courchesne R, Lord C. Evidence of linkage between the serotonin transporter and autistic disorder [J]. Mol Phychiatry,1997,2:247-250.
[17]Veenstra-Vander W, Kim S. Transmission disequilibrium studies of the serotonin 5-HT(2A) receptor gene in autism [J]. Am J Medi Genet,2002,114(3):277-283.
[18]Hultman C, Sparen P, Cnattingus S. Perinatal Risk Factors for Infantile Autism [J]. Epidemiolog,2002,13(4):417-423.
[19]黄立宏,黄流清,杜亚松.自闭症的生物学病因研究[J].国外医学精神病学分册,2003,30(4)：252-254.
[20]张亚林.高级精神病学[M].长沙：中南大学出版社,2006：643-647.
[21]Wilkerson D, Volpe A, Dean R. Perinatal complications as predictors of infantile autism [J]. Int J Neurosci,2002,112(9):1085-1098.
[22]Ingram J, Peckham S, Tisdale B. Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism [J]. Neurotoxicol Teratol,2000,22(2):319-324.
[23]Rice D, Barone S. Critical periods of vulnerability for the developing nervous system:evidence from humans and animal models [J]. Environ Health Perspect, 2000,108(3):511-533.
[24]Hallene K L, Oby E, Lee B J. Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations [J] [J]. Neuroscience Research,2006, 142(2):267-283.
[25]Padhye U. Excess dietary iron is the root cause for increase in childhood autism and allergies [J] [J]. Medicine hypotheses,2003,61(2):220-222.
[26]Halsey N, Hyman S. Measles-mumps-rubella vaccine and autistic spectrum disorder:report from the new challenges in childhood immunizations conference convener oak brook [J]. Illinoi Pediatrics,2001,107(1):E84.
[27]Reichelt K, Hole K, Hamberger A. Biologically active peptide-containing fractions in schizophrenia and childhood autism [J]. Adv Biochem Psychopharmacol,1981, 28:627-643.
[28]Ek J, Stensrud M, Reichelt K. Gluten-free diet decreases urinary peptide levels in children with celiac disease [J]. J Pediatr Gastroenterol Nutr,1999,29(3): 282-285.
[29]Knivsberg A, Reichelt K, Hoien T. A randomized controlled study of dietary intervention in autistic syndromes [J]. Nutr Neurosci,2002,5(4):251-261.
[30]Wakefield A, Puleston J, Montgomery S. The concept of entero-colonic encephalopathy, autism and opioid receptor ligands [J]. Aliment Pharmacol Ther, 2002,16(4):663-674.
[31]Bauman M, Kemper T. Neuroanatomic observations of the brain in autism[A].见: Bauman MLKemper TL. The neurobiology of autism [M][M]. Baltimore:Johns Hopkins University Press,1994:119-145.
[32]Bauman M, Kemper T. Structural brain anatomy in autism:what is the evidence? [J]. The Neurobiology of Autism,2004,12:119-145.
[33]Carper R, Moses P, Tigue Z, Courchesne E. Cerebral lobes in autism:Early hyperplasia and abnormal age effects [J]. Neuroimage,2002,16(4):1038-1051.
[34]Courchesne E. Brain development in autism:early overgrowth followed by premature arrest of growth [J]. Ment Retard Dev Disabil Res Rev,2004,10(1): 106-111.
[35]Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism [J]. JAMA,2003,290(3):337-344.
[36]Courchesne E, Karns C, Davis H. Unusual brain growth patterns in early life in patients with autistic disorder [J]. Neurology,2001,57(1):245-254.
[37]E. Courchesne, K. Pierce. Brain overgrowth in autism during a critical time in development:implications for frontal pyramidal neuron and interneuron development and connectivity [J]. Int J Dev Neurosci,2005,23 (2-3):153-170.
[38]HY Z. Postnatal Neurodevelopmental Disorders:Meeting at the Synapse? [J]. Science,2003,302:826-830.
[39]Katherine A L, Jocelyne B, Deborah A. Fronto-limbic Functioning in Children and Adolescents With and Without Autism [J]. Neuropsychologia,2008,46(1):49-62.
[40]Celio M. Parvalbumin in most gamma-aminobutyric acid-containing neurons of the rat cerebral cortex [J]. Science,1986,231(4741):995-997.
[41]王维霞,王月华,陈明军,上野照子,小野武年,西条寿夫,李瑞锡,彭裕文.PV阳性神经元在孤独症模型大鼠情绪与认知相关脑区内的表达[J].神经解剖学杂志,2008,24(2)：131-140.
[42]Bailey A. A clinicopathological study of autism [J]. Brain,1998,121:889-905.
[43]Kemper T, Bauman M. The contribution of neuropathologic studies to the understanding of autism [J]. Neurol Clin,1993,11:175-187.
[44]Fatemi S, Halt A, Stary J. Glutamic acid decarboxylase 65 and 67kDa proteins are reduced in autistic parietal and cerebellar cortices [J]. Biol Psychiatry,2002,52: 805-810.
[45]Shinohe A, Hashimoto K, Nakamura K. Increased serum levels of glutamate in adult patients with autism [J]. Neuro-Psychopharmacol Biol Psychiatry,2006,30: 1472-1477.
[46]Hussman J. Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism [J]. J Autism Dev Disord,2001,31:247-248.
[47]Polleux F, Lauder J. Toward a developmental neurobiology of autism [J]. Ment Retard Dev Disabil Res Rev,2004,10(1):303-317.
[48]Nelson W, Nusse R. Convergence of Wnt,β-Catenin, and Cadherin Pathways [J]. Science,2004,303:1483-1487.
[49]Wassink T, Piven J, Vieland V, Huang J, Swiderski R, Pietila J, Braun T, Beck G, Folstein S, Haines J L, Sheffield V. Evidence supporting WNT2 as an autism susceptibility gene [J]. Am J Med Genet,2001,105(5):406-413.
[50]Lijam N, Paylor R, McDonald M, Crawley J, Deng C, Herrup K, Stevens K, Maccaferri G, McBain C, Sussman D, WynshawBoris A. Social interaction and sensorimotor gating abnormalities in mice lacking Dvll [J]. Cell,1997,90(5): 895-905.
[51]陈明军,于剑锋,柴继侠,徐理,王中平,李瑞锡,彭裕文.Wnt通路信号蛋白β-catenin和GSK-3 β在孤独症模型大鼠脑中表达的变化[J].神经解剖学杂志,2009,25(4)：361-368.
[52]Gilmore E, Herrup K. Cortical development:Receiving Reelin [J]. Current Biology,2000,10:R162-R166.
[53]Meyer G, Goffinet A. Prenatal development of Reelin-immunoreactive neurons in the human neocortex [J]. J Comp Neurol,1998,396:29-40.
[54]Fatemi S, Snow A, Stary J, Araghi-Niknam M, Brooks A, Pearce D, Reutiman T, Lee S. Reelin signalling is impaired in autism [J]. Biol Psychiatry,2005,57: 777-787.
[55]Fatemi S. Reelin mutations in mouse and man:from reeler mouse to schizophrenia, mood disorders, autism and lissencephaly [J]. Mol Psychiatry,2001,6:129-133.
[56]Impagnatiello F, Guidotti A, Pesold C, Dwivedi Y, Caruncho H, Pisu M. A decrease of reelin expression as a putative vulnerability factor in schizophrenia [J]. Proc Natl Acad Sci USA,1998,95:15718-15723.
[57]Fatemi S, Earle J. Reduction in reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression [J]. Mol Psychiatry,2000,5:654-663.
[58]Persico A, Agruma L, Maiorano N. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder [J]. Mol Psychiatry,2001,6(2):150-159.
[59]Dutta S, Guhathakurta S, Sinha S. Reelin gene polymorphisms in the Indian population:a possible paternal 5'UTR-CGG-repeat-allele effect on autism [J]. Am J Med Genet B Neuropsychiatr Genet,2007,144(1):106-112.
[60]Serajee F, Zhong H, Mahbubul Huq A. Association of reelin gene polymorphisms with autism [J]. Genomics,2006,87(1):75-83.
[61]Skaar D, Shao Y, Haines J. Analysis of the RELN gene as a genetic risk factor for autism [J]. Mol Psychiatry,2005,10(6):563-571.
[62]Lawler C, Croen L, Grether J. Identifying environmental contributions to autism: provocative clues and false leads [J]. Ment Retard Dev Disabil Res Rev,2004, 10(2):292-302.
[63]Vliet J, Oates N, Law W. Epigenetic mechanisms in the context of complex diseases [J]. Cell Mol Life Sci,2007,64(4):1531-1538.
[64]Tchurikov N. Molecular mechanisms of epigenetics [J]. Biochemistry (Moscow), 2005,74(4):406-423.
[65]Fraga M, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Aydon C, Ropero S, Petrie K. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer [J]. Nat Genet,2005,37(2):391-400.
[66]Frigola J, Song J, Stirzaker C, Hinshelwood R, Peinado M, Clark S. Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band [J]. Nat Genet,2006,38(2):540-549.
[67]Wolffe A, Jones P, Wade P. DNA methylation [J]. PNAS,1999,96(11): 5894-5896.
[68]Fuks F. DNA methylation and histone modifications:teaming up to silence genes [J]. Curr Opin Genet Dev,2005,15(2):191-199.
[69]Okano M, Bell D, Haber D. DNA methyltransferases DNMT3a and DNMT3b are essential for de novo methylation and mammalian development [J]. Cell,1999, 99(1):247-257.
[70]Thatcher K, Peddada S, Yasui D, Lasalle J. Homologous pairing of 15q11-13 imprinted domains in brain is developmentally regulated but deficient in Rett and autism samples [J]. Hum Mol Genet,2005,14(3):785-797.
[71]Samaco R, Hogart A, LaSalle J. Epigenetic overlap in autism-spectrum neurodevelopmental disorders:MECP2 deficiency causes reduced expression of UBE3A and GABRB3 [J]. Hum Mol Genet,2005,14(2):483-492.
[72]Hagerman R, Ono M, Hagerman P. Recent advances in fragile X:a model for autism and neurodegeneration [J]. Curr Opin Psychiatry,2005,18(2):490-496.
[73]Schneider T, Przewlocki R. Behavioral alterations in rats prenatally exposed to valproic acid:Animal model of autism [J]. Neuropsychopharmacology,2005, 30(1):80-89.
[74]Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh J. Fetal valproate syndrome and autism:additional evidence of an association [J]. Dev Med Child Neurol,2001,43(3):202-206.
[75]Nanson J. Autism in fetal alcohol syndrome:a report of six cases [J]. Alcohol Clin Exp Res,1992,16(2):558-565.
[76]Nelson K, Bauman M. Thimerosal and autism? [J]. Pediatrics,2003,12(3): 674-679.
[77]Tazumi T, Hori E, Uwano T. Effects of prenatal maternal stress by repeated cold environment on behavioral and emotional development in the rat offspring [J]. Behav Brain Res,2005,162(1):153-160.
[2]张建娜.儿童孤独症的诊断与治疗现状[J].中国医刊,2005,40(4)：5-8.
[3]Muhle R, Trentacoste SV, Rapin I. The genetics of autism [J]. Pediatrics,2004,113 (5):e472-486.
[4]Dawson G, Webb S, Schellenberg G, Dager S, Friedman S, Aylward E, Richards T. Defining the broader phenotype of autism:genetics, brain, and behavioral perspectives [J]. Dev Psychopathol,2002,14 (3):581-611.
[5]Miller MT, Stromland K, Ventura L, Johansson M, Bandim JM, Gillberg C. Autism associated with conditions characterized by developmental errors in early embryogenesis:a mini review [J] Int J Dev Neurosci,2005,23 (2-3):201-219.
[6]Gutknecht L. Full-genome scans with autistic disorder [J]. Behavior genetics,2001, 31(1):113-123.
[7]Philippe A, Martinez M, Guilloud-Bataille M, Gillberg C, Rastam M, Sponheim E, Coleman M, Zappella M, Aschauer H, Van Maldergem L, Penet C, Feingold J, Brice A, Leboyer M. Genome-wide scan for autism susceptibility genes. Paris Autism Research International Sibpair Study [J]. Hum Mol Genet,1999,8 (5): 805-812.
[8]Freitag CM. The genetics of autistic disorders and its clinical relevance:a review of the literatur [J]. Mol Psychiatry,2007,12 (1):2-22.
[9]Wilkerson DS. Volpe AG, Dean RS, et al. Perinatal complications as predictors of infantile autism [J]. Int J Neurosci,2002,112 (9):1085-1098.
[10]Hultman CM, Sparen P. Cnattingus S. Perinatal risk factors for infantile autism [J]. Epidemiology,2002,13 (4):417-423.
[11]Reichelt KL, Hole K, Hamberger A, Saelid G, Edminson PD, Braestrup CB, Lingjaerde O, Ledaal P, H. O. Biologically active peptide-containing fractions in schizophrenia and childhood autism [J]. Adv Biochem Psychopharmacol,1981, 28:627-643.
[12]Ingram JL, Peckham SL, Tisdale B, P.M. R. Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism [J]. Neurotoxicol teratol,2000,22 (3):319-324.
[13]Schneider T, Przewlocki R. Behavioral alterations in rats prenatally exposed to valproic acid:Animal model of autism [J]. Neuropsychopharmacology,2005,30 (1):80-89.
[14]Wagner GC, Reuhl KR, Cheh M, McRae P, Halladay AK. A new neurobehavioral model of autism in mice:Pre-and postnatal exposure to sodium valproate [J]. J Autism Dev Disord,2006,36 (6):779-793.
[15]Christianson AL, Chesler N, Kromberg JG. Fetal valproate syndrome:clinical and neuro-developmental features in two sibling pairs [J]. Dev Med Child Neurol, 1994,36 (4):361-369.
[16]Ornoy A. Valproic acid in pregnancy:how much are we endangering the embryo and fetus? [J]. Reprod Toxicol,2009,28 (1):1-10.
[17]Hallene KL, Oby E, Lee BJ, Santaguida S, Bassanini S, Cipolla M, Marchi N, Hossain M, Battaglia G, Janigro D. Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations [J]. Neuroscience,2006,142 (1): 267-283.
[18]Schumacher HJ, Terapane J, Jordan RL, Wilson JG. The teratogenic activity of a thalidomide analogue, EM 12 in rabbits, rats, and monkeys [J]. Teratology,1972, 5 (2):233-240.
[19]Stromland K, Nordin V, Miller M, Akerstrom B, Gillberg C. Autism in thalidomide embryopathy:a population study [J]. Dev Med Child Neurol,1994,36 (4): 351-356.
[20]Padhye U. Excess dietary iron is the root cause for increase in childhood autism and allergies [J]. Med Hypotheses,2003,61 (1):220-222.
[21]Halsey NA, Hyman SL. Measles-mumps-rubella vaccine and autistic spectrum disorder:report from the new challenges in childhood immunizations conference convener oak brook [J]. Illinoi Pediatrics,2001,107 (1):E84.
[22]Stanfield AC, McIntosh AM, Spencer MD, Philip R, Gaur S, Lawrie SM. Towards a neuroanatomy of autism:A systematic review and meta-analysis of structural magnetic resonance imaging studies [J]. Eur Psychiatry,2008,23 (4):1-11.
[23]Palmen SJ, Engeland H, Hof PR. Neuropathogical findings in autism [J]. Brain, 2004,127 (12):2572-2583.
[24]Minshew NJ, Williams DL. The new neurobiology of autism [J]. Arch neurol, 2007,64 (7):945-950.
[25]Palmen SJMC, van Engeland H, Hof PR, Schmitz C. Neuropathological findings in autism [J]. Brain,2004,127 (Pt 12):2572-2583.
[26]Dean C, Dresbach T. Neuroligins and neurexins:linking cell adhesion, synapse formation and cognitive function [J]. Trends Neurosci,2006,29 (1):21-29.
[27]Polleux F, Lauder JM. Toward a developmental neurobiology of autism [J]. Ment Retard Dev Disabil Res Rev,2004,10 (4):303-317.
[28]Nelson WJ, Nusse R. Convergence of Wnt, P-Catenin, and Cadherin Pathways [J]. Science,2004,303 (5663):1483-1487.
[29]McEntee MF, Chiu CH, Whelan J. Relationship of β-catenin and Bcl-2 expression to sulindac-induced regression of intestinal tumors in Min mice [J]. Carcinogenesis,1999,20 (4):635-640.
[30]Davies NM, Watson MS. Clinical pharmacokinetics of sulindac:A dynamic old drug [J]. Clin Pharmacokinet,1997,32 (6):437-459.
[31]Rice PL, Kelloff J, Sullivan H, Driggers LJ, Beard KS, Kuwada S, Piazza G, Ahnen DJ. Sulindac metabolites induce caspase-and proteasome-dependent degradation of catenin protein in human colon cancer cells [J]. Mol Cancer Ther, 2003,2 (9):885-892.
[32]Wassink TH, Piven J, Vieland VJ, Huang J, Swiderski RE, Pietila J, Braun T, Beck G, Folstein SE, Haines JL, Sheffield VC. Evidence supporting WNT2 as an autism susceptibility gene [J]. Am J Med Genet,2001,105 (5):406-413.
[33]Lijam N, Paylor R, McDonald MP, Crawley JN, Deng CX, Herrup K, Stevens KE, Maccaferri G, McBain CJ, Sussman DJ, WynshawBoris A. Social interaction and sensorimotor gating abnormalities in mice lacking Dvll [J]. Cell,1997,90 (5): 895-905.
[34]陈明军,于剑锋,柴继侠,徐理,王中平,李瑞锡,彭裕文.Wnt通路信号蛋白β-catenin和GSK-3 β在孤独症模型大鼠脑中表达的变化[J].神经解剖学杂志,2009,25(4)：361-368.
[35]Lawler CP, Croen LA, Grether JK. Identifying environmental contributions to autism:provocative clues and false leads [J]. Ment Retard Dev Disabil Res Rev, 2004,10 (2):292-302.
[36]Vliet J, Oates NA, Law W. Epigenetic mechanisms in the context of complex diseases [J]. Cellular and molecular life sciences,2007,64 (4):1531-1538.
[37]Schanen NC. Epigenetics of autism spectrum disorders [J]. Hum Mol Genet,2006, 15 R138-R150.
[38]Tchurikov NA. Molecular mechanisms of epigenetics [J]. Biochemistry (Mosc), 2005,70 (4):406-423.
[39]Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, aydon C, Ropero S, Petrie K. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer [J]. Nat Genet,2005,37 (2):391-400.
[40]Frigola J, Song J, Stirzaker C, Hinshelwood RA, Peinado MA, Clark SJ. Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band [J]. Nat Genet,2006,38 (2):540-549.
[41]Ting AH, Schuebel KE, Herman JG, Baylin S. Short double-stranded RNA induces transcriptional gene silencing in human cancer cells in the absence of DNA methylation [J]. Nat Genet,2005,37 (3):906-910.
[42]Wolffe AP, Jones PL, Wade PA. DNA methylation [J]. PNAS,1999,96 (11): 5894-5896.
[43]Okano M, Bell DW, D.A. H. DNA methyltransferases DNMT3a and DNMT3b are essential for de novo methylation and mammalian development [J]. Cell,1999,99 (1):247-257.
[44]Fuks F. DNA methylation and histone modifications:teaming up to silence genes [J]. Curr Opin Genet Dev,2005,15 (2):191-199.
[45]Levenson JM, Roth TL, Lubin FD, Miller CA, Huang IC, Desai P, Malone LM, J.D. S. Evidence that DNA (Cytosine-5) methyltrans-ferase regulates synaptic plasticity in the hippocampus [J]. J Biol Chem,2006,281 (23):15763-15773.
[46]Santos F, Dean W. Epigenetic reprogramming during early development in mammals [J] Reproduction,2004,127 (2):643-651.
[47]Samaco RC, Hogart A, LaSalle JM. Epigenetic overlap in autism-spectrum neurodevelopmental disorders:MECP2 deficiency causes reduced expression of UBE3A and GABRB3 [J]. Hum Mol Genet,2005,14 (2):483-492.
[48]Thatcher KN, Peddada S, Yasui DH, Lasalle JM. Homologous pairing of 15q11-13 imprinted domains in brain is developmentally regulated but deficient in Rett and autism samples [J]. Hum Mol Genet,2005,14 (3):785-797.
[49]Rice D, Barone SJ. Critical periods of vulnerability for the developing nervous system:evidence from humans and animal models [J]. Environ Health Perspect, 2000,108 (Suppl 3):511-533.
[50]Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh JH. Fetal valproate syndrome and autism:additional evidence of an association [J]. Dev Med Child Neurol,2001,43 (3):202-206.
[51]Miyazaki K, Narita N, Narita M. Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring:implication for pathogenesis of autism [J]. Int J Dev Neurosci,2005,23 (2-3):287-297.
[52]Arndt TL, Stodgell CJ, Rodier PM. The teratology of autism [J]. Int J Dev Neurosci,2005,23 (2-3):189-199.
[53]Tunnicliff G. Actions of sodium valproate on the central nervous system [J]. J Physiol Pharmacol,1999,50 (3):347-365.
[54]Rasalam AD, Hailey H, Williams JHG, Moore SJ, Turnpenny PD, Lloyd DJ, Dean JCS. Characteristics of fetal anticonvulsant syndrome associated autistic disorder [J]. Dev Med Child Neurol,2005,47 (8):551-555.
[55]Wegner C, Nau H. Alteration of embryonic folate metabolism by valproic acid during organogenesis:implication for mechanism of teratogenesis [J]. Neurology, 1992,42 (Suppl.5):17-24.
[56]Bachevalier J, Loveland KA. The orbitofrontal-amygdala circuit and self-regulation of social-emotional behavior in autism [J]. Neuroscience and Biobehavioral Reviews,2006,30 (1):97-117.
[57]Katherine AL, Jocelyne B, Deborah A. Fronto-limbic Functioning in Children and Adolescents With and Without Autism [J]. Neuropsychologia,2008,46 (1): 49-62.
[58]Amaral DG, Schumann CM, Nordahl CW Neuroanatomy of autism [J]. Trends Neurosci,2008,31 (3):137-145.
[59]Nanson JL. Autism in fetal alcohol syndrome:a report of six cases [J]. Alcohol Clin Exp Res,1992,16 (2):558-565.
[60]Nelson KB, Bauman ML. Thimerosal and autism? [J]. Pediatrics,2003,12 (3): 674-679.
[61]Tazumi T, Hori E, Uwano T, Umeno K, Tanebe K, Tabuchi E, Ono T, Nishijo H. Effects of prenatal maternal stress by repeated cold environment on behavioral and emotional development in the rat offspring [J]. Behav Brain Res,2005,162 (1):153-160.
[62]王维霞,王月华,陈明军,上野照子,小野武年,西条寿夫,李瑞锡,彭裕文.PV阳性神经元在孤独症模型大鼠情绪与认知相关脑区内的表达[J].神经解剖学杂志,2008,24(2)：131-140.
[63]Carper RA, Moses P, Tigue ZD, Courchesne E. Cerebral lobes in autism:Early hyperplasia and abnormal age effects [J]. Neuroimage,2002,16 (4):1038-1051.
[64]Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism [J]. JAMA,2003,290 (3):337-344.
[65]Courchesne E, Pierce K. Brain overgrowth in autism during a critical time in development:implications for frontal pyramidal neuron and interneuron development and connectivity [J]. Int J Dev Neurosci,2005,23 (2-3):153-170.
[66]Belmonte MK, Cook EH, Anderson GM. Autism as a disorder of neural information processing:Directions for research and targets for therapy [J]. Mol Psychiatry,2004,9 (2):646-663.
[67]Sadamatsu M, Kanai H, Xu X, Liu Y, Kato N. Review of animal models for autism: implication of thyroid hormone [J]. Congenit Anom (Kyoto),2006,46 (1):1-9.
[68]Courchesne E, Karns C, H. D. Unusual brain growth patterns in early life in patients with autistic disorder [J]. Neurology,2001,57 (1):245-254.
[69]Lee M, Martin-Ruiz C, Graham A. Nicotinic receptor abnormalities in the cerebellar cortex in autism [J]. Brain,2002,125 (4):1483-1495.
[70]Allen G, Courchesne E. Differential effects of developmental cerebellar abnormality on cognitive and motor functions in the cerebellum:An fMRI study of autism [J]. Am J Psychiatry,2003,160 (1):262-273.
[71]Kates WR, Burnette CP, Eliez S. Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism [J]. Am J Psychiatry,2004, 161 (2):539-546.
[72]Courchesne E. Brain development in autism:early overgrowth followed by premature arrest of growth [J]. Ment Retard Dev Disabil Res Rev,2004,10 (2): 106-111.
[73]Dahl C, Guldberg P. DNA methylation analysis techniques [J]. Biogerontology, 2003,4 (4):233-250.
[74]Hagerman RJ, Ono MY, Hagerman PJ. Recent advances in fragile X:a model for autism and neurodegeneration [J]. Curr Opin Psychiatry,2005,18 (2):490-496.
[75]Fukuchi M, Nii T, Ishimaru N, Minamino A, Hara D, Takasaki I, Tabuchi A, Tsuda M. Valproic acid induces up-or down-regulation of gene expression responsible for the neuronal excitation and inhibition in rat cortical neurons through its epigenetic actions [J]. Neuroscience Research,2009,65 (1):35-43.
[76]Milutinovic S, D'Alessio AC, Detich N, Szyf M. Valproate induces widespread epigenetic reprogramming which involves demethylation of specific genes [J]. Carcinogenesis,2007,28 (3):560-571.
[77]Detich N, Bovenzi V, Szyf M. Valproate induces replication-independent active DNA demethylation [J]. J Biol Chem,2003,278 (30):27586-27592.
[78]Panhuysen M, Vogt WDM, Blanquet V, Brodski C, Heinzmann U, Beisker W, Wurst W. Effects of Wnt1 signaling on proliferation in the developing mid-/hindbrain region [J]. Mol Cell Neurosci,2004,26 (1):101-111.
[79]Ciani L, Salinas PC. WNTs in the vertebrate nervous system:from patterning to neuronal connectivity [J]. Nat Rev Neurosci,2005,6 (5):351-362.
[80]De Ferrari GV, Moon RT. The ups and downs of Wnt signaling in prevalent neurological disorders [J]. Oncogene,2006,25 (57):7545-7553.
[81]Chenn A, Walsh CA. Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta-catenin overexpressing transgenic mice [J]. Cereb Cortex,2003,13 (6):599-606.
[82]Brault V, Moore R, Kutsch S, Ishibashi M, Rowitch DH, McMahon AP, Sommer L, Boussadia O, Kemler R. Inactivation of the beta-catenin gene by Wntl-Cre-mediated deletion results in dramatic brain malformation and failure of craniofacial development [J]. Development,2001,128 (8):1253-1264.
[83]Guilland JC, Favier A, Potier de Courcy G, Galan P, Hercberg S. Hyper-homocysteinemia:An independent risk factor or a simple marker of vascular disease? [J]. Pathol Biol,2003,51:101-110.
[84]Lee ME, Wang H. Homocysteine and hypomethylation. A novel link to vascular disease [J]. Trends Cardiovasc Med,1999,9:49-54.
[85]Clarke S. Protein methylation [J]. Curr Opin Cell Biol,1993,5:977-983.
[86]Yerby MS. Management issues for women with epilepsy. Neural tube defects and folic acid supplementation [J]. Neurology,2003,61 (6 Suppl 2):S23-26.
[87]Wegner C, Nau H. Diurnal variation of folate concentrations in mouse embryo and plasma:the protective effect of folinic acid on valproic acid induced teratogenicity is time dependent [J]. Reprod Toxicol,1991,5 (6):465-471.
[88]Courchesne E, Pierce K, Schumann CM, Redcay E, Buckwalter JA, Kennedy DP, Morgan J. Mapping Early Brain Development in Autism [J]. Neuron,2007,56 399-413.
[89]Hazlett HC, Poe M, Gerig G, Smith RG, Provenzale J, Ross A, Gilmore J, Piven J. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years [J]. Arch Gen Psychiatry,2005,62:1366-1376.
[90]Ritvo ER, Freeman BJ, Scheibel AB, Duong T, Robinson H, Guthrie D. Lower Purkinje cell counts in the cerebella of four autistic subjects:initial findings of the UCLA-NSAC autopsy research report [J]. Am J Psychiatry,1986,143:862-876.
[91]Bauman ML, Kemper TL. Neuroanatomic observations of the brain in autism. In: Bauman ML, Kemper TL, editors. The neurobiology of autism [M]. Baltimore: Johns Hopkins University Press,1994:119-145.
[92]Buxbaum JD, Cai G, Chaste P. Mutation screening of the PTEN gene in patients with autism spectrum disordem and maclrocephaly [J]. Am J Med Genet B (Neuropsychiatr Genet),2007,144:484-491.
[93]Campos VE, Du M, Li Y. Increased seizure susceptibility and cortical malformation in β-catenin mutant mice [J]. Biochem Biophys Res Commun,2004, 320 (2):606-614.
[94]Endo Y, Rubin JS. Wnt signaling and neurite outgrowth:insights and questions. Cancer Sci,2007,98 (9):1311-1317.
[95]Cotter D, Kerwin R, al-Sarraji S, Brion JP, Chadwich A, Lovestone S. Abnormalities of Wnt signalling in schizophrenia-evidence for neurodevelopmental abnormality [J]. NeuroRep,1998,9 1379-1383.
[96]Hall AC, Lucas FR, Salinas PC. Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling [J]. Cell,2000,100 (5): 525-535.
[97]Patapoutian A, Reichardt LF. Roles of Wnt proteins in neural development and maintenance [J]. Curr Opin Neurobiol,2000,10 (3):392-399.
[98]Asghari V, Wang JF, Reiach JS, Young LT. Differential effects of mood stabilizers on Fos/Jun proteins and AP-1 DNA binding activity in human neuroblastoma SH-SY5Y cells [J]. Mol Brain Res,1998,58 (1-2):95-102.
[99]Prithviraj R, Kelly KM, Espinoza-Lewis R, Hexom T, Clark AB, Inglis FM. Differential regulation of dendrite complexity by AMPA receptor subunits GluR1 and GluR2 in motor neurons [J]. Dev Neurobiol,2008,68 (2):247-264.
[100]Frackowiak J, Cohen IL, Jenkins E, Flory M, Mazur-Kolecka B. Formation of neuronal processes in a cell culture model of neuronal differentiation in autism [J]. Int J Dev Neurosci,2006,24 (8):533-533.
[101]Koornstra JJ, Rijcken FEM, Oldenhuis CNAM, Zwart N, van der Sluis T, Hollema H, De Vries EGE, Keller JJ, Offerhaus JA, Giardiello FM, Kleibeuker JH. Sulindac inhibits β-catenin expression in normal-appearing colon of hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis patients [J]. Cancer Epidemiol Biomarkers Prev,2005,14 (7):1608-1612.
[102]Boon EMJ, Keller JJ, Wormhoudt TAM, Giardiello2 FM, Offerhaus1 GJA, van der Neut R, Pals ST. Sulindac targets nuclear Offerhaus-catenin accumulation and Wnt signaling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines [J]. Br J Cancer,2004,90 (1):224-229.
[1]DiCicco-Bloom E, Lord C, Zwaigenbaum L, Courchesne E, Dager S, Schmitz C, Schultz R, Crawley J, Young L. The developmental neurobiology of autism spectrum disorder [J]. J Neurosci,2006,26(26):6897-6906.
[2]Ballaban-Gil K, Tuchman R. Epilepsy and epileptiform EEG:Association with autism and language disorders [J]. Ment Retard Dev Disabil Res Rev,2000,6: 300-308.
[3]张建娜.儿童孤独症的诊断与治疗现状[J].中国医刊,2005,40(4)：5-8.
[4]Webbs D, Schellenbery G. Defining the broader phenotype of autism:genetics, brain, and behavioral perspectives [J]. Dev Psychopathol,2002,14(9):581-611.
[5]Bailey A, Le Couteur A, Gottesman I. Autism as a strongly genetic disorder: evidence from a British twin study [J]. Psychol Med,1995,25:63-77.
[6]Jorde L, Hassted S, Ritvo E. Complex segregation analysis of autism [J]. Am J Hum Genet,1991,49:932-938.
[7]Rutter M. Genetic Studies of Autism:From the 1970s into the Millennium [J]. J Abnormal Child Paychol,2000,28:3-14.
[8]Gutknecht L. Full-genome scans with autistic disorder [J]. Behavior genetics, 2001,31(1):113-123.
[9]Philippe A. Paris autism research International sibpair study:genome-wide scan for autism susceptibility genes [J]. Hum mol geneti,1999,8(1):805-812.
[10]Freitag C. The genetics of autistic disorders and its clinical relevance:a review of the literatur [J]. Mol psychiatry,2007,12(1):1-22.
[11]Rubenstein J, Merzenich M. Model of autism:increased ratio of excitation/inhibition in key neural systems [J]. Genes, Brain and Behavior,2003, 2:255-267.
[12]Buxbaum J, Silverman J, Smith C. Association between a GABARB3 polymorphism and autism [J]. Mol psychiatry,2002,7:311-316.
[13]Meldrum B. Glutamate as a neurotransmitter in the brain:review of physiology and pathology [J].J Nutr,2000,130:s1007-s1015.
[14]Jamain S, Betancur C, Quach H. Linkage and association of the glutamate receptor 6 gene with autism [J]. Mol Psychiatry,2002,7:217-220.
[15]Leboyer M, Philippe A, Bouvard M. Whole blood serotonin and plasma beta-endourphin in autistic probands and their first-degree relatives [J]. Biol psychiatry,1999,45(2):158-163.
[16]Cook E, Courchesne R, Lord C. Evidence of linkage between the serotonin transporter and autistic disorder [J]. Mol Phychiatry,1997,2:247-250.
[17]Veenstra-Vander W, Kim S. Transmission disequilibrium studies of the serotonin 5-HT(2A) receptor gene in autism [J]. Am J Medi Genet,2002,114(3):277-283.
[18]Hultman C, Sparen P, Cnattingus S. Perinatal Risk Factors for Infantile Autism [J]. Epidemiolog,2002,13(4):417-423.
[19]黄立宏,黄流清,杜亚松.自闭症的生物学病因研究[J].国外医学精神病学分册,2003,30(4)：252-254.
[20]张亚林.高级精神病学[M].长沙：中南大学出版社,2006：643-647.
[21]Wilkerson D, Volpe A, Dean R. Perinatal complications as predictors of infantile autism [J]. Int J Neurosci,2002,112(9):1085-1098.
[22]Ingram J, Peckham S, Tisdale B. Prenatal exposure of rats to valproic acid reproduces the cerebellar anomalies associated with autism [J]. Neurotoxicol Teratol,2000,22(2):319-324.
[23]Rice D, Barone S. Critical periods of vulnerability for the developing nervous system:evidence from humans and animal models [J]. Environ Health Perspect, 2000,108(3):511-533.
[24]Hallene K L, Oby E, Lee B J. Prenatal exposure to thalidomide, altered vasculogenesis, and CNS malformations [J] [J]. Neuroscience Research,2006, 142(2):267-283.
[25]Padhye U. Excess dietary iron is the root cause for increase in childhood autism and allergies [J] [J]. Medicine hypotheses,2003,61(2):220-222.
[26]Halsey N, Hyman S. Measles-mumps-rubella vaccine and autistic spectrum disorder:report from the new challenges in childhood immunizations conference convener oak brook [J]. Illinoi Pediatrics,2001,107(1):E84.
[27]Reichelt K, Hole K, Hamberger A. Biologically active peptide-containing fractions in schizophrenia and childhood autism [J]. Adv Biochem Psychopharmacol,1981, 28:627-643.
[28]Ek J, Stensrud M, Reichelt K. Gluten-free diet decreases urinary peptide levels in children with celiac disease [J]. J Pediatr Gastroenterol Nutr,1999,29(3): 282-285.
[29]Knivsberg A, Reichelt K, Hoien T. A randomized controlled study of dietary intervention in autistic syndromes [J]. Nutr Neurosci,2002,5(4):251-261.
[30]Wakefield A, Puleston J, Montgomery S. The concept of entero-colonic encephalopathy, autism and opioid receptor ligands [J]. Aliment Pharmacol Ther, 2002,16(4):663-674.
[31]Bauman M, Kemper T. Neuroanatomic observations of the brain in autism[A].见: Bauman MLKemper TL. The neurobiology of autism [M][M]. Baltimore:Johns Hopkins University Press,1994:119-145.
[32]Bauman M, Kemper T. Structural brain anatomy in autism:what is the evidence? [J]. The Neurobiology of Autism,2004,12:119-145.
[33]Carper R, Moses P, Tigue Z, Courchesne E. Cerebral lobes in autism:Early hyperplasia and abnormal age effects [J]. Neuroimage,2002,16(4):1038-1051.
[34]Courchesne E. Brain development in autism:early overgrowth followed by premature arrest of growth [J]. Ment Retard Dev Disabil Res Rev,2004,10(1): 106-111.
[35]Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism [J]. JAMA,2003,290(3):337-344.
[36]Courchesne E, Karns C, Davis H. Unusual brain growth patterns in early life in patients with autistic disorder [J]. Neurology,2001,57(1):245-254.
[37]E. Courchesne, K. Pierce. Brain overgrowth in autism during a critical time in development:implications for frontal pyramidal neuron and interneuron development and connectivity [J]. Int J Dev Neurosci,2005,23 (2-3):153-170.
[38]HY Z. Postnatal Neurodevelopmental Disorders:Meeting at the Synapse? [J]. Science,2003,302:826-830.
[39]Katherine A L, Jocelyne B, Deborah A. Fronto-limbic Functioning in Children and Adolescents With and Without Autism [J]. Neuropsychologia,2008,46(1):49-62.
[40]Celio M. Parvalbumin in most gamma-aminobutyric acid-containing neurons of the rat cerebral cortex [J]. Science,1986,231(4741):995-997.
[41]王维霞,王月华,陈明军,上野照子,小野武年,西条寿夫,李瑞锡,彭裕文.PV阳性神经元在孤独症模型大鼠情绪与认知相关脑区内的表达[J].神经解剖学杂志,2008,24(2)：131-140.
[42]Bailey A. A clinicopathological study of autism [J]. Brain,1998,121:889-905.
[43]Kemper T, Bauman M. The contribution of neuropathologic studies to the understanding of autism [J]. Neurol Clin,1993,11:175-187.
[44]Fatemi S, Halt A, Stary J. Glutamic acid decarboxylase 65 and 67kDa proteins are reduced in autistic parietal and cerebellar cortices [J]. Biol Psychiatry,2002,52: 805-810.
[45]Shinohe A, Hashimoto K, Nakamura K. Increased serum levels of glutamate in adult patients with autism [J]. Neuro-Psychopharmacol Biol Psychiatry,2006,30: 1472-1477.
[46]Hussman J. Suppressed GABAergic inhibition as a common factor in suspected etiologies of autism [J]. J Autism Dev Disord,2001,31:247-248.
[47]Polleux F, Lauder J. Toward a developmental neurobiology of autism [J]. Ment Retard Dev Disabil Res Rev,2004,10(1):303-317.
[48]Nelson W, Nusse R. Convergence of Wnt,β-Catenin, and Cadherin Pathways [J]. Science,2004,303:1483-1487.
[49]Wassink T, Piven J, Vieland V, Huang J, Swiderski R, Pietila J, Braun T, Beck G, Folstein S, Haines J L, Sheffield V. Evidence supporting WNT2 as an autism susceptibility gene [J]. Am J Med Genet,2001,105(5):406-413.
[50]Lijam N, Paylor R, McDonald M, Crawley J, Deng C, Herrup K, Stevens K, Maccaferri G, McBain C, Sussman D, WynshawBoris A. Social interaction and sensorimotor gating abnormalities in mice lacking Dvll [J]. Cell,1997,90(5): 895-905.
[51]陈明军,于剑锋,柴继侠,徐理,王中平,李瑞锡,彭裕文.Wnt通路信号蛋白β-catenin和GSK-3 β在孤独症模型大鼠脑中表达的变化[J].神经解剖学杂志,2009,25(4)：361-368.
[52]Gilmore E, Herrup K. Cortical development:Receiving Reelin [J]. Current Biology,2000,10:R162-R166.
[53]Meyer G, Goffinet A. Prenatal development of Reelin-immunoreactive neurons in the human neocortex [J]. J Comp Neurol,1998,396:29-40.
[54]Fatemi S, Snow A, Stary J, Araghi-Niknam M, Brooks A, Pearce D, Reutiman T, Lee S. Reelin signalling is impaired in autism [J]. Biol Psychiatry,2005,57: 777-787.
[55]Fatemi S. Reelin mutations in mouse and man:from reeler mouse to schizophrenia, mood disorders, autism and lissencephaly [J]. Mol Psychiatry,2001,6:129-133.
[56]Impagnatiello F, Guidotti A, Pesold C, Dwivedi Y, Caruncho H, Pisu M. A decrease of reelin expression as a putative vulnerability factor in schizophrenia [J]. Proc Natl Acad Sci USA,1998,95:15718-15723.
[57]Fatemi S, Earle J. Reduction in reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression [J]. Mol Psychiatry,2000,5:654-663.
[58]Persico A, Agruma L, Maiorano N. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder [J]. Mol Psychiatry,2001,6(2):150-159.
[59]Dutta S, Guhathakurta S, Sinha S. Reelin gene polymorphisms in the Indian population:a possible paternal 5'UTR-CGG-repeat-allele effect on autism [J]. Am J Med Genet B Neuropsychiatr Genet,2007,144(1):106-112.
[60]Serajee F, Zhong H, Mahbubul Huq A. Association of reelin gene polymorphisms with autism [J]. Genomics,2006,87(1):75-83.
[61]Skaar D, Shao Y, Haines J. Analysis of the RELN gene as a genetic risk factor for autism [J]. Mol Psychiatry,2005,10(6):563-571.
[62]Lawler C, Croen L, Grether J. Identifying environmental contributions to autism: provocative clues and false leads [J]. Ment Retard Dev Disabil Res Rev,2004, 10(2):292-302.
[63]Vliet J, Oates N, Law W. Epigenetic mechanisms in the context of complex diseases [J]. Cell Mol Life Sci,2007,64(4):1531-1538.
[64]Tchurikov N. Molecular mechanisms of epigenetics [J]. Biochemistry (Moscow), 2005,74(4):406-423.
[65]Fraga M, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Aydon C, Ropero S, Petrie K. Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer [J]. Nat Genet,2005,37(2):391-400.
[66]Frigola J, Song J, Stirzaker C, Hinshelwood R, Peinado M, Clark S. Epigenetic remodeling in colorectal cancer results in coordinate gene suppression across an entire chromosome band [J]. Nat Genet,2006,38(2):540-549.
[67]Wolffe A, Jones P, Wade P. DNA methylation [J]. PNAS,1999,96(11): 5894-5896.
[68]Fuks F. DNA methylation and histone modifications:teaming up to silence genes [J]. Curr Opin Genet Dev,2005,15(2):191-199.
[69]Okano M, Bell D, Haber D. DNA methyltransferases DNMT3a and DNMT3b are essential for de novo methylation and mammalian development [J]. Cell,1999, 99(1):247-257.
[70]Thatcher K, Peddada S, Yasui D, Lasalle J. Homologous pairing of 15q11-13 imprinted domains in brain is developmentally regulated but deficient in Rett and autism samples [J]. Hum Mol Genet,2005,14(3):785-797.
[71]Samaco R, Hogart A, LaSalle J. Epigenetic overlap in autism-spectrum neurodevelopmental disorders:MECP2 deficiency causes reduced expression of UBE3A and GABRB3 [J]. Hum Mol Genet,2005,14(2):483-492.
[72]Hagerman R, Ono M, Hagerman P. Recent advances in fragile X:a model for autism and neurodegeneration [J]. Curr Opin Psychiatry,2005,18(2):490-496.
[73]Schneider T, Przewlocki R. Behavioral alterations in rats prenatally exposed to valproic acid:Animal model of autism [J]. Neuropsychopharmacology,2005, 30(1):80-89.
[74]Williams G, King J, Cunningham M, Stephan M, Kerr B, Hersh J. Fetal valproate syndrome and autism:additional evidence of an association [J]. Dev Med Child Neurol,2001,43(3):202-206.
[75]Nanson J. Autism in fetal alcohol syndrome:a report of six cases [J]. Alcohol Clin Exp Res,1992,16(2):558-565.
[76]Nelson K, Bauman M. Thimerosal and autism? [J]. Pediatrics,2003,12(3): 674-679.
[77]Tazumi T, Hori E, Uwano T. Effects of prenatal maternal stress by repeated cold environment on behavioral and emotional development in the rat offspring [J]. Behav Brain Res,2005,162(1):153-160.