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

• 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
• 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

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.

项目摘要/摘要 X连锁自闭症谱系障碍Rett综合征（RTT）是毁灭性的儿童残疾，具有 对个人（1：10,000分），他们的家庭和社会的巨大影响。大多数RTT案件是 由编码甲基-CPG结合蛋白2（MECP2）的基因中功能丧失突变引起的。 RTT女孩 出生时没有任何明显的问题，但突然出现了许多神经系统缺陷，包括不规则 呼吸，有目的的手动和言语，癫痫发作和智力残疾。其中 症状，运动功能障碍和注意力相关行为转移的缺陷是最深刻的， 与基底神经节的几种脑疾病相似。疾病改良疗法 设计用于治疗RTT的设计需要清楚地了解 分子，细胞和网络水平。纹状体的功能障碍，大多数输入进入基底神经节， 可能在RTT发病机理中起重要作用。纹状体接收谷氨酸能兴奋性预测 从丘脑，整合和调节皮质输入以进行适当的纹状体输出。我们的初步数据 展示了MECP2敲除（KO）小鼠中丘脑 - 纹状体突触的功能和可塑性的改变， 可能导致皮质 - 纹状体突触的功能障碍。我们的假设是改变了丘脑纹状体 MECP2 KO小鼠中的突触功能在整合皮质输入中的纹状体作用。我们 提出了两个具体目的：（1）表征丘脑神经元及其突触投影 MECP2 KO小鼠的纹状体； （2）测试丘脑输入对背侧皮质纹状体系统的影响 纹状体在MECP2 KO小鼠中受损。我们预计这些实验将产生新的信息 关于MECP2损失对丘脑纹状体突触传播和可塑性的后果以及 关于其整合和控制皮质 - 纹状体连接。这些发现将发现基本的大脑 RTT神经病理学涉及的机制以及开发和测试新型治疗方法的帮助。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底物，包括亨廷顿和帕金森氏病，以及 图雷特和安吉尔曼综合征。