Olivocerebellar Circuitry in Autism

自闭症患者的橄榄小脑回路

• 批准号: 7923926
• 负责人: GENE J BLATT
• 金额: $ 75.69万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923926
• 关键词: AMPA Receptors; Address; Adult; Affect; Affinity; Age; Algorithms; Amino Acid Transporter; Anterior; Area; Aspartate; Autistic Disorder; Autopsy; Behavior; Behavioral; Behavioral Symptoms; Biological Assay; Brain; Candidate Disease Gene; Cerebellar cortex structure; Cerebellar vermis structure; Cerebellum; Clinical; Cognitive; Communication; Complement; Computer software; Cues; Data; Defect; Development; Devices; Diagnostic; Disease; Emotional; Evaluation; Excitatory Amino Acids; Fiber; Funding; GABA Receptor; GLAST Protein; Gender; Glutamate Receptor; Glutamate Transporter; Glutamates; Golgi Apparatus; Grant; Histocytochemistry; Human; Hyperplasia; Immunofluorescence Immunologic; Immunohistochemistry; In Situ Hybridization; Individual; Interview; Investigation; Label; Laboratories; Language; Lateral; Left; Lesion; Letters; Ligand Binding; Linear Regressions; Link; Lobe; Lobule; Long-Term Depression; Long-Term Potentiation; Measures; Membrane; Mental Depression; Messenger RNA; Metabotropic Glutamate Receptors; Methods; Microscopic; Molecular; Motor; Myoepithelial cell; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; Nature; Neuroglia; Neurons; Patients; Pharmaceutical Preparations; Phenotype; Process; Progress Reports; Property; Purkinje Cells; Reciprocal Social Interaction; Regulation; Reporting; Role; Sensorimotor functions; Sensory; Severities; Slide; Social Controls; Social Interaction; Source; Stereotyped Behavior; Stereotyping; Symptoms; Synapses; Synaptophysin; System; Techniques; Tissues; association cortex; autistic children; base; behavior measurement; cognitive function; density; developmental disease; flexibility; gray matter; improved; innovation; insight; interest; mind control; mossy fiber; nerve supply; neurochemistry; novel; postsynaptic; presynaptic; programs; public health relevance; receptor; receptor binding; receptor expression; relating to nervous system; social; social communication; stellate cell; translational approach; transmission process; white matter

Autism is a developmental disorder and affected individuals have alterations in brain function disrupting their ability to perform particular motor and cognitive tasks. The main long term objective of this project is to determine in one major affected brain region, the cerebellum, how changes in connectivity at the synaptic level are disturbed based on errors in the early development of key afferent projections and target neurons. Glutamatergic mossy fibers, olivocerebellar climbing fibers and parallel fibers all synapse on key cerebellar cortical neurons, some of which show neuropathological changes in autism. The major objective of this study focuses on key glutamatergic transporters and receptors in two functionally distinct parts of the cerebellar cortex, the Crus II area in the posterior lobe recently implicated in cognitively-based functions and vermis lobule VI in the anterior lobe important for sensorimotor-based roles. Quantitative glutamatergic measures will be related to scores from the Autism Diagnostic Interview-Revised (ADI-R) for reciprocal social interaction, communication, and stereotyped and repetitive motor behavior domains. To accomplish these objectives, four specific aims are proposed in ten adult (age 16-30 years old) autistic post-mortem cases and ten age-, gender and postmortem interval-matched controls. The first specific aim, to be completed in the first year, uses histological ligand binding to determine the number and ligand binding affinity of key ionotropic (AMPAR, NMDAR) and metabotropic glutamate receptors (mGluR1) in the three laminae of Crus II and lobule VI, targets for cerebellar afferents. The second specific aim, to be completed in the first year, uses in situ hybridization histochemistry in the same cerebellar regions to quantify the mRNA levels of three types of postsynaptic glutamate receptor subtypes (AMPAR1, NMDAR1 and mGluR1). The third specific aim with trials in the first year and completed in the second year, quantifies the densities of key glutamate transporters at terminals ending on PCs (Le., excitatory amino acid transporter type 4, EAAT4; on membranes of Bergmann glia that predominately wrap around climbing synapses (EAA T1, L-glutamate/L-aspartate transporter, GLAST); and a glutamate receptor (GluRo2) that is important for induction of long-term depression (LTD) and is predominately localized to parallel fiber synapses on PCs. Co-localization of GluRo2 with PSD93 will determine the percentage of postsynaptic density and co-localization of EAAT4 with synaptophysin will determine the percentage of presynaptic density. The final specific aim, to be completed in the second year, takes a translational approach and evaluates the relationships of glutamate receptors, transporters and synaptic density to severity of social-communicative and repetitive behavior symptoms as measured by the Autism Diagnostic Interview - Revised (ADI-R). This aim examines whether significant changes in key excitatory glutamate component(s) in the two functionally distinct cerebellar regions relate differentially to autism symptom type and severity in the clinical cases. Data from these studies over the two year project will help delineate core neural substrates in autistic individuals and should help guide geneticists in their search for possible candidate genes in the disorder. Furthermore, understanding the cellular and molecular mechanisms within this model region could contribute to our understanding of current pharmacotherapeutic treatments of autistic individuals and may suggest novel treatments targeted to neural substrates.

自闭症是一种发育障碍，受影响的个体大脑功能发生改变，破坏了他们执行特定运动和认知任务的能力。该项目的主要长期目标是确定在一个主要受影响的大脑区域（小脑）中，突触水平连接的变化是如何根据关键传入投射和目标神经元早期发育中的错误而受到干扰的。谷氨酸能苔藓纤维、橄榄小脑攀爬纤维和平行纤维都是关键小脑皮质神经元上的突触，其中一些显示自闭症的神经病理学变化。这项研究的主要目标集中在小脑皮质两个功能不同部分的关键谷氨酸转运蛋白和受体，后叶的小腿 II 区域最近与认知功能有关，前叶的蚓小叶 VI 对感觉运动很重要。基础角色。定量谷氨酸测量将与自闭症诊断访谈修订版 (ADI-R) 的分数相关，涉及相互的社交互动、沟通以及刻板和重复的运动行为领域。为了实现这些目标，在 10 名成人（16-30 岁）自闭症死后病例和 10 名年龄、性别和死后间隔匹配的对照中提出了四个具体目标。第一个具体目标将在第一年完成，利用组织学配体结合来确定 Crus II 和小叶 VI 三个层中关键离子型（AMPAR、NMDAR）和代谢型谷氨酸受体（mGluR1）的数量和配体结合亲和力，小脑传入的目标。第二个具体目标将在第一年完成，在相同的小脑区域使用原位杂交组织化学来量化三种突触后谷氨酸受体亚型（AMPAR1、NMDAR1 和 mGluR1）的 mRNA 水平。第三个具体目标是在第一年进行试验并在第二年完成，量化 PC 末端关键谷氨酸转运蛋白的密度（即，兴奋性氨基酸转运蛋白 4 型，EAAT4；在主要包裹的伯格曼神经胶质细胞膜上）攀爬突触（EAA T1，L-谷氨酸/L-天冬氨酸转运蛋白，GLAST）和谷氨酸受体（GluRo2）； GluRo2 与 PSD93 的共定位将决定突触后密度的百分比，而 EAAT4 与突触素的共定位将决定突触前的百分比。最终的具体目标将在第二年完成，采用转化方法并评估谷氨酸受体、转运蛋白和谷氨酸受体的关系。突触密度与社会交流和重复行为症状严重程度的关系，通过自闭症诊断访谈 - 修订版 (ADI-R) 进行测量。该目的检查两个功能不同的小脑区域中关键兴奋性谷氨酸成分的显着变化是否与临床病例中的自闭症症状类型和严重程度存在差异相关。这些为期两年的研究项目的数据将有助于描绘自闭症个体的核心神经基质，并应有助于指导遗传学家寻找该疾病中可能的候选基因。此外，了解该模型区域内的细胞和分子机制可能有助于我们了解当前自闭症患者的药物治疗，并可能提出针对神经基质的新治疗方法。

项目成果

Density of cerebellar basket and stellate cells in autism: evidence for a late developmental loss of Purkinje cells.

• DOI: 10.1002/jnr.22056
• 发表时间: 2009-08-01
• 期刊: JOURNAL OF NEUROSCIENCE RESEARCH
• 影响因子: 4.2
• 作者: Whitney, Elizabeth R.;Kemper, Thomas L.;Rosene, Douglas L.;Bauman, Margaret L.;Blatt, Gene J.
• 通讯作者: Blatt, Gene J.

Increased GAD67 mRNA expression in cerebellar interneurons in autism: implications for Purkinje cell dysfunction.

自闭症小脑中间神经元中 GAD67 mRNA 表达增加：对浦肯野细胞功能障碍的影响。

• DOI: 10.1002/jnr.21520
• 发表时间: 2008
• 期刊: Journal of neuroscience research
• 影响因子: 4.2
• 作者: Yip,Jane;Soghomonian,Jean-Jacques;Blatt,GeneJ
• 通讯作者: Blatt,GeneJ

Alterations in GABAergic biomarkers in the autism brain: research findings and clinical implications.

• DOI: 10.1002/ar.21252
• 发表时间: 2011-10
• 期刊: ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY
• 影响因子: 2
• 作者: Blatt, Gene J.;Fatemi, S. Hossein
• 通讯作者: Fatemi, S. Hossein

Autism spectrum disorders and neuropathology of the cerebellum.

• DOI: 10.3389/fnins.2015.00420
• 发表时间: 2015
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Hampson DR;Blatt GJ
• 通讯作者: Blatt GJ

Calbindin-D28k is a more reliable marker of human Purkinje cells than standard Nissl stains: a stereological experiment.

Calbindin-D28k 是比标准尼氏染色更可靠的人类浦肯野细胞标记：体视学实验。

• DOI: 10.1016/j.jneumeth.2007.09.009
• 发表时间: 2008
• 期刊: Journal of neuroscience methods
• 影响因子: 3
• 作者: Whitney,ElizabethR;Kemper,ThomasL;Rosene,DouglasL;Bauman,MargaretL;Blatt,GeneJ
• 通讯作者: Blatt,GeneJ