Parvalbumin-Containing Neurons in Schizophrenia

精神分裂症中含有小白蛋白的神经元

• 批准号: 8426153
• 负责人: TSUNG-UNG W. WOO
• 金额: $ 33.79万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 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/8426153
• 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

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.

描述（由申请人提供）：精神分裂症（SZ）中含有钙结合蛋白小清蛋白（PV）的抑制性神经元的神经回路发生功能性改变。此外，它似乎是通过N-甲基-D-天冬氨酸（NMDA）受体在PV神经元的多巴胺能神经传递在前额叶皮层（PFC）可能是不足的SZ。在本申请中，我们将研究是否其他谷氨酸受体亚基，包括AMPA（1-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯）GluR 2亚基和代谢型I组谷氨酸受体mGluR 1或5亚基，或多巴胺D1受体可能有助于NMDA神经传递缺陷。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Kv3.1b和Kv3.2的表达减少，这在赋予PV神经元快速发放特性中起关键作用。因此，我们将使用免疫印迹技术来检测两种促进氧化应激的酶，烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶（Nox）和神经元型一氧化氮合酶（nNOS），以及抗氧化酶谷氨酸半胱氨酸连接酶的催化和调节亚基。我们还将检测白细胞介素6的mRNA表达，白细胞介素6激活Nox的产生，从而促进氧化应激，在PV神经元中。此外，我们将测量PV神经元中Kv3.1b和Kv3.2的mRNA，以观察它们是否可能在SZ中减少。由于PV神经元被富含硫酸软骨素蛋白多糖的神经元束膜网（PNNs）包裹，这被认为在维持其功能完整性方面起着至关重要的作用，我们将研究SZ中PNNs的数量是否会减少。最后，据推测，在围青春期PV神经元的赤字可能脱轨的轨迹皮质成熟，有助于SZ的发病。我们将探讨转录调控PV神经元电路在SZ和正常围青春期人类PFC的发展，以深入了解SZ发病的可能分子机制。两者合计，从拟议的实验结果将提高我们的理解SZ的病理生理和分子机制，可能有助于其发病。因此，它们可能导致治疗和预防策略的概念化，这些策略旨在从根本上纠正或重新校准功能失调的PV神经元回路。