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.

项目概要 唐氏综合症 (DS) 是由人类 21 号染色体 (Hsa21) 的第三个拷贝引起的，大约每人中就有 1 人患有唐氏综合症 (DS)。 美国有 700 名新生儿出生 DS 是遗传性智力障碍的主要原因，具有严重影响 关于公共卫生。已经提出了几种关于 DS 认知障碍的神经发育假说， 但最引人注目的之一是 DS 的 GABA 能假说，该假说假设 GABA 的改变 早期大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，一个 DS 小鼠模型，Dp(16)1Yey/+ 小鼠（以下称为 Dp16），显示出在患有以下疾病的患者中观察到的类似缺陷： DS，包括减少的皮质 GABA 能中间神经元。尽管前额皮质（PFC）在 DS 患者的高级认知过程和 PFC 中观察到的功能障碍，目前知之甚少 关于介导改变的 GABA 能神经元的有害影响的神经生物学机制 关于 DS 中 PFC 发展和认知的活动。为了理解这些损伤是如何产生的， 有必要首先了解大脑 GABA 能调节的基本细胞和突触机制 功能以及它们在 DS 大脑中如何改变。在这个 R21 提案中，我们利用了一种新颖的工具组合 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 检验我们的中心假设，即抑制性神经元活动的减少会削弱 GABA 能突触， 通过 Dp16 PFC 中的异质突触串扰诱导异常兴奋性突触成熟。在我们的指导下 强有力的初步数据，我们将在两个具体目标中检验这一假设：1）确定 Dp16 小鼠是否 表现出 2/3 层锥体神经元抑制性和兴奋性突触的结构和功能改变 在 PFC 中。 2)确定抑制活性在Dp16的PFC中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我们对独特而详细的机制的理解 GABA 调节大脑发育，与 PFC 功能障碍的细胞基础至关重要 DS 中的智力障碍。我们预计我们的结果将突出调查的新途径 DS 的病理生理学是由 GABA 信号传导的早期扰动引起的。