A new approach to understanding cognitive disabilities in Down syndrome

理解唐氏综合症认知障碍的新方法

• 批准号: 10725562
• 负责人: Won Chan Oh
• 金额: $ 42.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725562
• 关键词: Acceleration; Action Potentials; Address; Area; Behavior; Birth; Brain; Characteristics; Chromosome 21; Cognition; Cognitive; Data; Development; Disease; Down Syndrome; Electroencephalography; Electrophysiology (science); Equilibrium; Excitatory Synapse; Exhibits; Functional disorder; Future; GABA Receptor; Genes; Genetic; Genetic Suppression; Glutamates; Goals; Hippocampus; Human; Human Chromosomes; Image; Impairment; Inhibitory Synapse; Intellectual functioning disability; Interneurons; Investigation; Link; Mediating; Modeling; Mus; Neurobiology; Neurons; Patients; Persons; Prefrontal Cortex; Public Health; Receptor Signaling; Regulation; Role; Signal Transduction; Structure; Synapses; Synaptic Transmission; Testing; Vertebral column; Whole-Cell Recordings; Work; aging hippocampus; cognitive disability; cognitive process; functional disability; gamma-Aminobutyric Acid; genetic approach; hippocampal pyramidal neuron; improved; improved outcome; in vivo; inhibitory neuron; mouse Ts65Dn; mouse model; neurobiological mechanism; neuronal circuitry; neuropathology; neurophysiology; novel; novel strategies; novel therapeutic intervention; pharmacologic; postsynaptic; synaptic function; tool; two photon microscopy; two-photon

Project Summary Down syndrome (DS), caused by a third copy of the human chromosome 21 (Hsa21), occurs in about 1 of every 700 births in the U.S. DS is the leading cause of genetically-defined intellectual disability, with a serious impact on public health. Several neurodevelopmental hypotheses for cognitive disabilities in DS have been proposed, but one of the most compelling is the GABAergic hypothesis for DS, which postulates that alterations in GABA signaling in early brain development may contribute to its neuropathology. Recent studies have found that a mouse model of DS, Dp(16)1Yey/+ mice (hereafter called Dp16), shows a similar deficit seen in patients with DS, including reduced cortical GABAergic interneurons. Despite the importance of prefrontal cortex (PFC) in higher cognitive processes and the observed functional impairments in PFC of people with DS, little is known about the neurobiological mechanisms that mediate the detrimental effects of altered GABAergic neuronal activity on PFC development and cognition in DS. In order to understand how these impairments arise, it is necessary to first understand the basic cellular and synaptic mechanisms of GABAergic regulation of brain function and how they are altered in the DS brain. In this R21 proposal, we utilize a novel combination of tools including two-photon microscopy, electrophysiology, chemogenetics, and in vivo pharmacological manipulation to test our central hypothesis that decreased inhibitory neuronal activity weakens GABAergic synapses and induces abnormal excitatory synapse maturation via heterosynaptic crosstalk in the PFC of Dp16. Guided by our strong preliminary data, we will examine this hypothesis in two specific aims: 1) Determine whether Dp16 mice exhibit structural and functional alterations of inhibitory and excitatory synapses on layer 2/3 pyramidal neurons in the PFC. 2) Determine the role of inhibitory activity in excitatory synapse maturation in the PFC of Dp16. Results from this exploratory study will further our understanding of the unique and detailed mechanisms by which GABA regulates brain development, with critical relevance to cellular underpinnings of PFC dysfunction and intellectual disability in DS. We expect that our results will highlight new avenues into the investigation of the pathophysiology underlying DS resulting from early perturbation of GABA signaling.

项目摘要 唐氏综合征（DS），由人类21号染色体（Hsa 21）的第三个拷贝引起，大约每100人中就有1人发生。 DS是遗传定义的智力残疾的主要原因，具有严重的影响 关于公共卫生的。已经提出了几种关于DS认知障碍的神经发育假说， 但其中最引人注目的是关于DS的GABA能假说，该假说假定GABA的改变 早期脑发育中的信号传导可能有助于其神经病理学。最近的研究发现， DS的小鼠模型，Dp（16）1 Yey/+小鼠（下文称为Dp 16），显示出在患有 DS，包括皮质GABA能中间神经元减少。尽管前额叶皮层（PFC）在 更高的认知过程和观察到的功能障碍，在PFC的人与DS，知之甚少 关于介导改变的GABA能神经元的有害作用的神经生物学机制， 活动PFC的发展和认知在DS。为了了解这些损伤是如何产生的， 首先需要了解大脑GABA能调节的基本细胞和突触机制 功能以及它们在DS大脑中的变化。在这个R21提案中，我们利用了一种新的工具组合， 包括双光子显微镜、电生理学、化学遗传学和体内药理学操作 为了验证我们的核心假设，即抑制性神经元活动减少会削弱GABA能突触， 通过Dp 16 PFC中的异突触串扰诱导异常兴奋性突触成熟。引导我们的 强有力的初步数据，我们将在两个特定的目标来检验这一假设：1）确定Dp 16小鼠是否 在第2/3层锥体神经元上表现出抑制性和兴奋性突触的结构和功能改变 2）确定抑制活性在Dp 16 PFC兴奋性突触成熟中的作用。 这项探索性研究的结果将进一步加深我们对独特和详细机制的理解， GABA调节大脑发育，与PFC功能障碍的细胞基础密切相关 和智力残疾。我们希望我们的研究结果将突出新的途径， GABA信号早期扰动导致DS的病理生理学基础。