Defective Thalamic Projections to Dorsal Striatum in Rett Syndrome

雷特综合征中丘脑背侧纹状体投射缺陷

基本信息

批准号：
9316052
负责人：
Wei Li
金额：
$ 22.28万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9316052
关键词：
Angelman Syndrome Attention Axon Basal Ganglia Basal Ganglia Diseases Behavioral Birth Brain Brain Diseases Breathing Cells Childhood Corpus striatum structure Data Disease Dopamine D1 Receptor Dopamine D2 Receptor Dorsal Family Frequencies Functional disorder Genes Genetic Transcription Gilles de la Tourette syndrome Glutamates Hand Huntington Disease Impairment Individual Intellectual functioning disability Knockout Mice Link Locomotion Magnetic Resonance Imaging Methyl-CpG-Binding Protein 2 Molecular Morphology Movement Mutation Neurologic Deficit Neurons Output Parafascicular Nucleus Parkinson Disease Pathogenesis Pathway interactions Performance Play Population Prediabetes syndrome Presynaptic Terminals Property Recycling Rett Syndrome Role Seizures Shapes Slice Societies Speech Stimulus Symptoms Synapses Synaptic Transmission Synaptic Vesicles Synaptic plasticity System Testing Thalamic structure Transgenic Mice autism spectrum disorder caudate nucleus common symptom density disability experimental study girls improved loss of function mutation motor deficit motor disorder motor impairment nervous system disorder neuropathology novel novel therapeutic intervention optogenetics postsynaptic presynaptic quantum relating to nervous system response selective expression spatial relationship synaptic function therapy design

项目摘要

PROJECT SUMMARY/ABSTRACT Rett syndrome (RTT), an X-linked autism spectrum disorder, is a devastating childhood disability and has a tremendous impact on individuals (1:10,000 births), their families and society. The majority of RTT cases are caused by loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (MeCP2). RTT girls are born without any obvious problems but abruptly develop a host of neurological deficits, including irregular breathing, loss of purposeful hand movement and speech, seizures, and intellectual disability. Among these symptoms, motor dysfunction and deficits in attention-related behavioral shifting are the most profound, bearing resemblance to several brain disorders of basal ganglia origin. Disease-modifying therapies that are designed for the treatment of RTT require a clear understanding of the underlying pathophysiology at the molecular, cellular, and network levels. Dysfunction of the striatum, where most inputs enter the basal ganglia, may play a significant role in RTT pathogenesis. The striatum receives glutamatergic excitatory projections from the thalamus, which integrate and modulate cortical inputs for proper striatal output. Our preliminary data demonstrate altered function and plasticity of thalamo-striatal synapses in Mecp2 knockout (KO) mice, which may contribute to dysfunction of cortico-striatal synaptic. Our hypothesis is that altered thalamo-striatal synaptic function in Mecp2 KO mice disintegrates the striatal role in integrating cortical inputs. We propose two Specific Aims: (1) characterize thalamic neurons and their synaptic projections to the dorsal striatum of Mecp2 KO mice; (2) test whether the impact of thalamic inputs on cortico-striatal system in dorsal striatum is impaired in Mecp2 KO mice. We anticipate that these experiments will yield novel information regarding the consequences of MeCP2 loss on thalamo-striatal synaptic transmission and plasticity, as well as on its integration and control of cortico-striatal connections. These findings will uncover fundamental brain mechanisms involved in RTT neuropathology, and aid to develop and test novel therapeutic approaches. Our studies will also have deep implications for the understanding and treatment of other neurological disorders with common symptoms and neural substrates, including Huntington and Parkinson diseases, as well as Tourette and Angelman syndromes.

项目概要/摘要雷特综合征 (RTT) 是一种 X 连锁自闭症谱系障碍，是一种毁灭性的儿童残疾，具有对个人（1：10,000 出生）、其家庭和社会产生巨大影响。大多数 RTT 案例是由编码甲基 CpG 结合蛋白 2 (MeCP2) 的基因功能丧失突变引起。 RTT女孩出生时没有任何明显的问题，但突然出现一系列神经缺陷，包括不规则的神经缺陷呼吸、丧失有目的的手部运动和言语、癫痫发作和智力障碍。其中症状、运动功能障碍和注意力相关行为转变的缺陷是最严重的，与基底神经节起源的几种脑部疾病相似。疾病修饰疗法是设计用于治疗 RTT 需要清楚地了解潜在的病理生理学分子、细胞和网络水平。纹状体功能障碍，大部分输入进入基底神经节，可能在 RTT 发病机制中发挥重要作用。纹状体接收谷氨酸能兴奋性投射来自丘脑，它整合和调节皮质输入以获得适当的纹状体输出。我们的初步数据证明 Mecp2 敲除 (KO) 小鼠丘脑纹状体突触的功能和可塑性发生改变，可能导致皮质纹状体突触功能障碍。我们的假设是丘脑纹状体的改变 Mecp2 KO 小鼠的突触功能破坏了纹状体在整合皮质输入中的作用。我们提出两个具体目标：（1）表征丘脑神经元及其向背侧的突触投射 Mecp2 KO 小鼠的纹状体； (2) 测试丘脑输入是否对背侧皮质纹状体系统的影响 Mecp2 KO 小鼠纹状体受损。我们预计这些实验将产生新的信息关于 MeCP2 缺失对丘脑纹状体突触传递和可塑性的影响，以及关于皮质纹状体连接的整合和控制。这些发现将揭示大脑的基本机制 RTT 神经病理学中涉及的机制，有助于开发和测试新的治疗方法。我们的研究还将对其他神经系统疾病的理解和治疗产生深远的影响具有常见症状和神经基质，包括亨廷顿病和帕金森病，以及抽动秽语综合症和天使综合症。