Parvalbumin-Containing Neurons in Schizophrenia

精神分裂症中含有小白蛋白的神经元

基本信息

批准号：
8214572
负责人：
TSUNG-UNG W. WOO
金额：
$ 35.19万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-08-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8214572
关键词：
Address Adolescent Adolescent Development Adult Age Agglutinins Antioxidants Award Bioinformatics Biotin Brain-Derived Neurotrophic Factor Buffers Calcium-Binding Proteins Cations Cell Adhesion Chondroitin Sulfate Proteoglycan Collaborations Cytoskeleton Data Analyses Development Digoxigenin Dopamine D1 Receptor Enzymes Extracellular Matrix Functional disorder GCLC gene Gene Chips Gene Expression Generations Genes Genetic Transcription Glutamate Receptor Glutamate-Cysteine Ligase Glutamates Goals Human Hydroxyl Radical Immunoblotting In Situ Hybridization Injury Integrins Interleukin-6 Isoxazoles Label Lead Lectin Light Link Major Histocompatibility Complex Measures Mediating Messenger RNA Metabotropic Glutamate Receptors MicroRNAs Molecular Molecular Profiling N-Methyl-D-Aspartate Receptors N-Methylaspartate NADP NADPH Oxidase National Cancer Institute Neurobiology Neuronal Dysfunction Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Nitric Oxide Synthase Type I Onset of illness Oxidases Oxidative Stress Parvalbumins Pathology Pathway interactions Play Polymerase Chain Reaction Potassium Channel Prefrontal Cortex Prevention strategy Process Production Property Propionates Pyramidal Cells Reactive Oxygen Species Role Schizophrenia Signal Transduction Staining method Stains Support Groups Synaptic plasticity Techniques Time Transcriptional Regulation Voltage-Gated Potassium Channel Wisteria base cohort density hippocampal pyramidal neuron human subject improved inhibitory neuron insight laser capture microdissection male nerve supply neural circuit neurobiological mechanism neurotransmission novel public health relevance research study treatment strategy voltage

项目摘要

DESCRIPTION (provided by applicant): Neural circuits of inhibitory neurons that contain the calcium-binding protein parvalbumin (PV) are functionally altered in schizophrenia (SZ). Furthermore, it appears that glutamatergic neurotransmission on PV neurons via the N-methyl-D-aspartate (NMDA) receptor in the prefrontal cortex (PFC) may be deficient in SZ. In this application, we will examine whether other glutamate receptor subunits, including the AMPA (1-amino- 3-hydroxyl-5-methyl-4-isoxazole-propionate) GluR2 subunit and the metabotropic group I glutamate receptor mGluR1 or 5 subunit, or the dopamine D1 receptor may contribute to NMDA neurotransmission deficiency. Deficient NMDA neurotransmission on PV neurons may further contribute to PV neuronal dysfunction via at least two mechanisms: oxidative stress and decreased expression of voltage-gated potassium channels Kv3.1b and Kv3.2, which play a critical role in conferring the fast-spiking properties to PV neurons. Hence, we will use immunoblot technique to examine two enzymes that promote oxidative stress, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) and neuronal nitric oxide synthase (nNOS), and the catalytic and modulatory subunits of the antioxidant enzyme glutamate cysteine ligase in homogenized PFC. We will also examine the expression of the mRNA for interleukin 6, which activates Nox production and thus promote oxidative stress, in PV neurons. In addition, we will measure the mRNA for Kv3.1b and Kv3.2 in PV neurons to see if they may be decreased in SZ. Because PV neurons are ensheathed by chondroitin sulfate proteoglycans-rich perineuronal nets (PNNs), which are thought to play a crucial role in maintaining their functional integrity, we will examine whether the number of PNNs may be decreased in SZ. Finally, it is postulated that deficits of PV neurons during the peri-adolescent period may derail the trajectories of cortical maturation, contributing to the onset of SZ. We will explore the transcriptional regulation of PV neuronal circuits both in SZ and during normal peri-adolescent human PFC development in order to gain insight into the possible molecular mechanisms of SZ onset. Taken together, findings from the proposed experiments will improve our understanding of the pathophysiology of SZ and the molecular mechanisms that may contribute to its onset. As such, they may lead to the conceptualization of treatment and prevention strategies that aim at fundamentally correcting or recalibrating the dysfunctional PV neuronal circuits. PUBLIC HEALTH RELEVANCE: The goal of this application is to improve our understanding of the molecular mechanisms that mediate the disturbances of inhibitory neural circuits in schizophrenia. Findings of the proposed studies are expected to shed light on the conceptualization of treatment and prevention strategies that aim at fundamentally correcting the underlying neural circuit deficits.

描述（由申请人提供）：含有钙结合蛋白白蛋白（PV）的抑制性神经元的神经回路在精神分裂症（SZ）中在功能上有所改变。此外，看来通过前额叶皮层（PFC）中N-甲基-D-天冬氨酸（NMDA）受体对PV神经元的谷氨酸神经传递可能在SZ中缺乏。在此应用中，我们将检查其他谷氨酸受体亚基，包括AMPA（1-氨基-3-羟基-5-甲基-4-异沙唑 - 丙酸）GLUR2亚基和代谢型I谷氨酸组MGLUR1或5个亚基索引，或者可能贡献N. glutamation群体MGLUR1或5个亚基D1受体。 PV神经元上的NMDA神经传递缺陷可能通过至少两种机制进一步导致PV神经元功能障碍：氧化应激和电压门控钾通道的表达降低KV3.1B和KV3.2，在将快速尖刺性特性赋予PV神经元中起着至关重要的作用。因此，我们将使用免疫印迹技术检查两种促进氧化应激的酶，烟酰胺腺苷二核苷酸磷酸（NADPH）氧化酶（NOX）（NOX）和神经元氧化物氧化酶（NNOS）（NNOS），以及抗抗氧化剂的催化性和催化性和催化性亚基的抗氧化剂。我们还将检查白介素6的mRNA的表达，该白介素6在PV神经元中激活NOX的产生并从而促进氧化应激。此外，我们将测量PV神经元中Kv3.1b和Kv3.2的mRNA，以查看SZ中是否可以减少它们。由于光伏神经元被软骨素硫酸盐蛋白聚糖蛋白聚糖蛋白神经元（PNN）（PNNS）所掩盖，被认为在维持其功能完整性方面起着至关重要的作用，因此我们将检查SZ中PNN的数量是否可能减少。最后，据推测，在青春期期间，PV神经元的缺陷可能会使皮质成熟的轨迹轨道轨迹，从而导致SZ的发作。我们将探讨SZ和正常围场的人类PFC发育中PV神经元回路的转录调节，以深入了解SZ发作的可能分子机制。综上所述，提出的实验的发现将提高我们对SZ病理生理学的理解以及可能有助于其发作的分子机制。因此，它们可能导致旨在从根本上纠正或重新校准功能失调的PV神经元电路的治疗和预防策略的概念化。公共卫生相关性：该应用的目的是提高我们对介导精神分裂症抑制性神经回路干扰的分子机制的理解。拟议研究的结果预计将阐明旨在从根本上纠正基本神经电路缺陷的治疗和预防策略的概念化。