Olivocerebellar Circuitry in Autism

自闭症患者的橄榄小脑回路

基本信息

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
项目类别：
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

项目摘要

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，受影响的个体在大脑功能方面发生了变化，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一个主要受影响的大脑区域，小脑，突触水平的连通性的变化如何根据关键传入预测和目标神经元的早期发展中的错误而受到干扰。谷氨酸能的苔藓纤维，橄榄球攀爬纤维和平行纤维均在关键小脑皮质神经元上突触，其中一些显示自闭症的神经病理学变化。这项研究的主要目的集中在小脑皮层功能不同部分的关键谷氨酸能转运蛋白和受体上，后叶的CRUS II面积最近与基于认知的功能有关，而在基于认知的叶子中，对基于感觉的较重要的是基于认知的叶子VI。定量谷氨酸能措施将与自闭症诊断访谈习惯（ADI-R）的分数有关，用于相互的社交互动，交流以及定型和重复的运动行为行为领域。为了实现这些目标，提出了十个成年人（16-30岁）自闭症后案件和十个年龄，性别和验证后匹配的对照组的四个具体目标。首个具体目标将在第一年完成，它使用组织配体结合来确定关键离子型（AMPAR，NMDAR）和代谢性谷氨酸酯受体（MGLUR1）的数量和配体结合，在Crus II和Lobule VI的三个层次中，CRUS II和LOBULE VI VI，Targets for Cerebellar for Cerebellar for Cerebellar arteresents for Cerebellar afferents for Cerebellar afferesters for crus ii和Lobule vi vi。第二个特定目标将在第一年完成，在同一小脑区域使用原位杂交组织化学来量化三种类型的突触后谷氨酸受体亚型的mRNA水平（AMPAR1，NMDAR1和MGLUR1）。第一个特定目标在第一年进行试验并在第二年完成，量化了终端处于端子上的关键谷氨酸转运蛋白的密度（LE。，兴奋性氨基酸转运蛋白4型，EAAT4；在伯格曼胶质的膜上；谷氨酸受体（Gluro2）对于诱导长期抑郁（LTD）很重要，并且在PC上的平行纤维共定位。一年，采用转化方法，并评估谷氨酸受体，转运蛋白和突触密度与社会交流和重复行为症状的严重程度的关系，如自闭症诊断访谈（ADI-R）所测量的。这个目的研究了两个在功能上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自闭症症状类型和严重程度有不同的关系。在两年项目中，这些研究的数据将有助于描绘自闭症患者的核心神经底物，并应帮助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对自闭症个体的当前药物治疗治疗的理解，并可能提出针对神经底物的新型治疗方法。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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