A new approach to understanding cognitive disabilities in Down syndrome

项目摘要 唐氏综合症(DS)，由人类21号染色体的第三个拷贝(Hsa21)引起，大约每隔一年就会发生一次 在美国出生的700人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。关于DS中认知障碍的几种神经发育假说已经被提出， 但其中最引人注目的是DS的GABA能假说，该假说假设GABA的变化 早期大脑发育中的信号可能与其神经病理有关。最近的研究发现， DS的小鼠模型，DP(16)1Yey/+小鼠(以下称为Dp16)，显示出类似的缺陷，在 DS，包括皮质GABA能中间神经元减少。尽管前额叶皮质(PFC)在 DS患者PFC的高级认知过程和观察到的功能损害，目前知之甚少 关于GABA能神经元损伤效应的神经生物学机制 DS患者PFC发育和认知的活动。为了了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大脑中是如何改变的。在这份R21提案中，我们使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物操作 为了验证我们的中心假设，即抑制性神经元活动减少会削弱GABA能突触和 在Dp16的PFC中通过异突触串扰诱导异常的兴奋性突触成熟。由我们的指导 强大的初步数据，我们将在两个特定的目标来检验这一假说：1)确定Dp16小鼠 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 在一等兵学校。2)确定抑制活性在Dp16的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而详细的机制的理解 哪种GABA调节大脑发育，与PFC功能障碍的细胞基础密切相关 以及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 导致DS的病理生理学基础是GABA信号的早期扰动。

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.