Chandellier interneurons and the excitation/inhibition balance in the human prefrontal cortex in autism

吊灯式中间神经元与自闭症患者前额叶皮层的兴奋/抑制平衡

• 批准号: 9349604
• 负责人: Veronica Martinez-Cerdeno
• 金额: $ 38.42万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-02 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9349604
• 关键词: Antibodies; Area; Autistic Disorder; Autopsy; Axon; Brain; Brodmann' s area; Carrier Proteins; Cell Count; Cells; Cerebral cortex; Characteristics; Data; Dimensions; Elements; Epilepsy; Equilibrium; Functional disorder; Funding; GABA Receptor; Goals; Golgi Apparatus; Grant; Human; Image; Immunochemistry; Impairment; Individual; Inhibitory Synapse; Interneurons; Label; Length; MFGE8 gene; Microscopy; Morphology; Neuroglia; Neurons; Output; Parvalbumins; Pathology; Patients; Prefrontal Cortex; Presynaptic Terminals; Property; Proteins; Publishing; Pyramidal Cells; Reporting; Research; Role; Schizophrenia; Severities; Staining method; Stains; Structure; Symptoms; Synapses; System; Technology; Temporal Lobe; Tissue Stains; Translating; Translational Research; base; case control; cell type; density; gamma-Aminobutyric Acid; high resolution imaging; hippocampal pyramidal neuron; nervous system disorder; neural circuit; novel; protein transport; receptor; reconstruction

Chandellier interneurons and the excitation/inhibition balance in the human prefrontal cortex in autism Little is known about the pathology of the cerebral cortex in autism. The goal of our previously funded R01 grant was to unravel the pathology of the cerebral cortex in patients with autism. Specifically, we proposed to discover which cell type(s), if any, are altered in the cerebral cortex of human autistic cases. We quantified the number of pyramidal neurons, specific subtypes of interneurons, and glial cells, within each layer of the human temporal and prefrontal cortex in autism. We determined that the number of pyramidal neurons and glial cells in the temporal cerebral cortex of autistic cases did not differ from that in typically developing control cases, and published our results in several research articles (Camacho et al., 2014; Kim et al., 2015). However, we discovered that there is a decrease in the number of one specific interneuronal subtype in the prefrontal cortex of autistic cases, the parvalbumin (PV)+ Chandellier cell (Hashemi et al., 2016). Chandellier (Ch) cells are the main interneuron in the cortex possessing axons that synapse directly on the initial segment of the pyramidal axon, creating a prominent structure called “cartridge”. Consequently, the Ch cell is the main interneuronal subtype that regulates the final output of excitatory projection neurons. Therefore, the loss of a small number of Ch cells may critically impair function of pyramidal cells and of the cerebral cortex as a whole. Indeed, changes in Ch cells cartridges/boutons and/or function have previously been reported in neurological diseases, such as schizophrenia and epilepsy. Based on our discovery, we propose to define the role of Ch cells in autism by unraveling their morphological and connectional properties. We hypothesize that the decreased number of PV+ Ch cells we discovered in the autistic cortex translates into a decrease in the number of Ch cell cartridges and a decrease in the number of synaptic buttons per cartridge, with the consequent loss of Ch symmetric synapses on the pyramidal neuron axonal initial segment, and ultimately impaired function of cortical projection neurons. We also hypothesize that there is a decreased amount of GABA and GABA related proteins per cartridge, and of GABRAα2 receptors in the pyramidal axonal initial segment. This reduction of inhibitory synapse structure would cause hyperexcitation of cortical synaptic circuits in autism. Additionally, we hypothesize that in autism there is a negative correlation between the severity of the patient' symptoms and the number of Ch cells. We will determine if there is an alteration in the number and length of Ch cell cartridges (Aim1), if there is an alteration in the GABAergic system in Ch cartridges (Aim 2), and if there is an alteration in the number of axo- axonic synapses (Aim 3) in the prefrontal cortex (BA9, BA45, BA46) of the autism postmortem brain. We will label cartridges and GABA related proteins with immunochemistry, Ch cells with Golgi staining, and analyze synapse structure with 3D electronic microscopy. We will analyze data using Stereoinvestigator, Neurolucida, Image J, FIB/SEM EM, and high-throughput 3D reconstruction. We will correlate data obtained for the autistic group (Aim 1-3) with specific symptoms and other patient characteristics. Providing a comprehensive quantification of the elements of the GABA system in the autism cerebral cortex is necessary to move the field of autism research in a new direction. This project will provide a thorough understanding of the GABAergic system in the human cerebral cortex in autism, and will have a great impact on translational research directed towards providing novel treatment for individuals with autism. !

自闭症中人类前额叶皮层的吊灯中间神经元和兴奋/抑制平衡 对自闭症中大脑皮层的病理知之甚少。我们以前资助的R01的目标 格兰特（Grant）是为了解散自闭症患者大脑皮层的病理。具体来说，我们提出了 发现在人体加速病例的大脑皮层中，哪种细胞类型（如果有）发生了变化。我们量化了 在人的每一层中，锥体神经元的数量，中间神经元的特定亚型和神经胶质细胞的数量 自闭症中的临时和前额叶皮层。我们确定了锥体神经元和神经胶质细胞的数量 在暂时的脑皮质中，令人印象深刻的病例与典型的控制病例没有差异， 并在几篇研究文章中发表了我们的结果（Camacho等，2014； Kim等，2015）。但是，我们 发现前额叶皮层中一种特定的一种特定神经元亚型的数量有所减少 在自闭症病例中，白蛋白（PV）+枝形吊灯细胞（Hashemi等，2016）。吊灯（CH）细胞是 皮质中的主要神经元，具有直接在金字塔的初始段的轴突 轴突，创建了一个名为“墨盒”的突出结构。因此，CH细胞是主要的神经元间 调节兴奋投影神经元最终输出的亚型。因此，损失少量 CH细胞可能会严重损害锥体细胞和整个大脑皮层的功能。确实，变化 在CHA细胞中，墨盒/胸子和/或功能以前已在神经系统疾病中报道过，例如 精神分裂症和癫痫。根据我们的发现，我们建议通过 揭示其形态和连接特性。 我们假设我们在加速皮层中发现的PV+ CH细胞数量减少了 CH细胞墨盒数量减少，每个墨盒的突触按钮数量减少， 随之而来的是在金字塔神经元轴突初始段上的CH对称突触的损失，并且 最终受损的皮质投射神经元功能。我们还假设有拒绝 每个墨盒的GABA和GABA相关蛋白的量，以及金字塔轴突中的Gabraα2受体的量 初始段。抑制性突触结构的减少将导致皮质突触过度过度 自闭症中的电路。此外，我们假设在自闭症中， 患者符号的严重程度和CH细胞的数量。 我们将确定CH细胞墨盒的数量和长度是否发生了变化（AIM1），是否存在 CH弹药筒中GABA能系统的改变（AIM 2），并且如果轴向数量发生了变化 自闭症后大脑的前额叶皮层（BA9，BA45，BA46）中的轴突突触（AIM 3）。我们将 标记墨盒和GABA与免疫化学，具有高尔基体染色的CH细胞相关的蛋白质，并分析 带有3D电子显微镜的突触结构。我们将使用立体评价器Neurolucida分析数据， 图像J，FIB/SEM EM和高通量3D重建。我们将关联到加速度获得的数据 具有特定症状和其他患者特征的组（AIM 1-3）。 提供自闭症大脑皮层中GABA系统元素的全面数量 需要将自闭症研究领域朝着新的方向发展。该项目将提供一个彻底的 了解自闭症中人类大脑皮层中的GABA能系统，并将产生很大的影响 关于翻译的研究，致力于为自闭症患者提供新颖的治疗。 呢