Neuronal heparan sulfate deficiency and autism

神经元硫酸乙酰肝素缺乏与自闭症

• 批准号: 7100655
• 负责人: YU YAMAGUCHI
• 金额: $ 19.1万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7100655
• 关键词: AMPA receptors; autism; behavior test; behavioral /social science research tag; developmental genetics; developmental neurobiology; electrophysiology; enzyme deficiency; gene mutation; genetic susceptibility; genetically modified animals; glutamate receptor; glycosyltransferase; heparan sulfate; heparin; in situ hybridization; laboratory mouse; neural transmission; neurogenetics; neurons; receptor expression; social behavior; tissue /cell culture

DESCRIPTION (provided by applicant): Heparan sulfate (HS) is a constituent of the cell surface and extracellular matrix and plays critical roles in various biological processes. This proposal will investigate our novel hypothesis that deficiency in neuronal cell surface HS can be a cause of social interaction deficits as seen in autistic spectrum disorders. This hypothesis is based on the following experimental and clinical observations: (1) HS is concentrated in synapses, regulates the maturation of synapses, and is involved in the expression of hippocampal synaptic plasticity. (2) Hereditary Multiple Exostosis (HME) is an autosomal dominant bone disorder that is caused by defective HS synthesis due to mutations of the GlcNAc/GIcA co-polymerase EXT1. Interestingly, there have been clinical reports indicating that HME patients associate autistic traits. Some of these cases carry only point mutations of EXT1, suggesting that mutations of EXT1 per se could cause autistic disorders. (3) Our analysis of EXT1 conditional knockout mice suggests that these mice have abnormal social behavior. (4) We found that the GluR1 subunit of AMPA-type glutamate receptors binds heparin, and that surface expression of AMPA receptors is drastically reduced in EXT1-deficient neurons in vitro. Abnormalities in the glutamate receptor system have been implicated as a potential cause of autism spectrum disorders. Based on these observations, we hypothesize that neuronal HS deficiency causes abnormal glutamatergic synaptic transmission, which in turn results in the development of autistic traits. In this project, we aim at demonstrating that genetic disruption of HS synthesis results in social interaction deficits and impaired glutamate receptor function of the animal. In Aim 1, we will perform detailed behavioral analysis on conditional EXT1 knockout mice to determine whether there is a correlation between HS deficiency and social and behavioral phenotypes. In Aim 2, using biochemical and electrophysiological approaches, we will examine whether the expression of functional glutamate receptors is impaired in EXT1-deficient neurons in vivo. Together, these aims should effectively answer whether there is a causative linkage between neuronal HS deficiency and the expression of autistic traits. If our hypothesis proves correct, this project will pave a way toward a new direction of autism research.

描述（由申请人提供）：硫酸乙酰肝素（HS）是细胞表面和细胞外基质的组成部分，在各种生物学过程中起着关键作用。该提议将调查我们的新假设，即神经元细胞表面HS缺乏可能是自闭症谱系障碍中社会相互作用缺陷的原因。该假设基于以下实验和临床观察：（1）HS集中在突触中，调节突触的成熟，并参与海马突触可塑性的表达。 （2）遗传性多重外胞病（HME）是一种常染色体显性骨疾病，是由于GLCNAC/GICA共糖浆酶Ext1的突变引起的HS合成缺陷引起的。有趣的是，有临床报告表明HME患者是自闭症特征。其中一些病例仅带有EXT1的点突变，这表明Ext1本身的突变可能引起自闭症疾病。 （3）我们对Ext1条件敲除小鼠的分析表明，这些小鼠具有异常的社会行为。 （4）我们发现AMPA型谷氨酸受体的GLUR1亚基结合肝素，并且在Ext1缺陷型神经元的体外，AMPA受体的表面表达大大降低。谷氨酸受体系统中的异常已被认为是自闭症谱系障碍的潜在原因。基于这些观察结果，我们假设神经元HS缺乏会导致异常的谷氨酸能突触传播，从而导致自闭症性状的发展。在这个项目中，我们旨在证明HS合成的遗传破坏会导致社会相互作用缺陷和动物的谷氨酸受体功能受损。在AIM 1中，我们将对条件Ext1敲除小鼠进行详细的行为分析，以确定HS缺乏与社会和行为表型之间是否存在相关性。在AIM 2中，使用生化和电生理方法，我们将检查在体内Ext1缺陷神经元中功能性谷氨酸受体的表达是否受损。总之，这些目标应该有效地回答神经元HS缺乏与自闭症性状表达之间是否存在致病联系。如果我们的假设证明是正确的，那么该项目将为自闭症研究的新方向铺平道路。