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Perineuronal proteolysis and circuit dysfunction in HAND

HAND 中的神经周围蛋白水解和回路功能障碍

基本信息

批准号：
10401844
负责人：
Katherine E Conant
金额：
$ 38.88万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401844
关键词：
Acute Affect Amino Acid Motifs Animals Astrocytes Attention Brain Brain Injuries CD34 gene Carbachol Cells Cerebrospinal Fluid Data Diffusion Disintegrins Event Extracellular Matrix Family member Functional disorder Gelatinase B Genetically Engineered Mouse Glutamate Receptor Glutamates HIV HIV Envelope Protein gp120 HIV Infections HIV-associated cognitive impairment Hippocampus (Brain)Human Immunofluorescence Immunologic Impaired cognition Impairment In Vitro Individual Inhibition of Matrix Metalloproteinases Pathway Injections Knock-out Label Lateral Learning Link Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Measures Mediating Memory Metalloproteases Microglia Modeling Molecular Mus Myoepithelial cell Neurons Pacemakers Parvalbumins Peptide Hydrolases Periodicity Peripheral Blood Mononuclear Cell Population Population Dynamics Proteins Proteolysis Publishing Pyramidal Cells Research Personnel SIV Sampling Slice Stimulus Stromelysin 1 Testing Therapeutic Thrombospondins Virus Diseases Western Blotting Whole-Cell Recordings Wild Type Mouse Work aggrecan antiretroviral therapy brain tissue brevican cell type collagenase 3 density gamma-Aminobutyric Acid in vivo inhibitor knockout animal long term memory memory consolidation mouse model nerve supply neuroimmunology neurophysiology population based presynaptic protein expression stem cells tat Protein therapeutic target virotoxins

项目摘要

Due to strong excitatory input, reliable GABA release and fast firing, parvalbumin expressing (PV) neurons are thought to represent critical pacemakers for synchronous network events. PV neurons also represent the predominant GABAergic neuronal population that is enveloped by the perineuronal net (PNN), a lattice like extracellular matrix that is thought to localize glutamatergic input. Disruption of the PNN has been linked to reductions in PV excitability. Importantly, deficits in PV excitability influence synchronous network events critical to both attention and long-term memory consolidation. In support of this, recent studies have demonstrated that reduced glutamatergic input to hippocampal PV cells, through knockout of PV selective glutamate receptors or a reduction in presynaptic glutamatergic innervation, is linked to increases in sharp wave ripple (SWR) density and deficits in long term memory consolidation. PNN processing occurs through the actions of specific proteases. While metalloproteinases of the “a disintegrin and metalloproteinase with thrombospondin motifs” (ADAMTS) and secreted matrix metalloproteinase (MMP) family members can cleave specific PNN components, the latter may be particularly important in the background of human immunodeficiency virus (HIV) infection. Soluble MMPs are expressed by neurons and microglia and known to digest PNN components including aggrecan and brevican. In addition, while ADAMTS protein expression is not detected in astrocytes in a simian immunodeficiency virus (SIV) model, PNN degrading MMPs are highly expressed by astrocytes, the most numerous cell type in the brain. Moreover, in murine models of brain injury, selective MMP inhibition reduces PNN remodeling. It has previously been demonstrated that human HIV encoded Tat protein can increase the expression and/or cellular release of MMP-9, a potent modulator of PNN processing. Tat protein is detectable in the cerebrospinal fluid of individuals receiving combination anti-retroviral treatment (cART). In new preliminary data included herein, we show that Tat significantly increases release of MMP-13 from astrocytes. Moreover, we see active forms of MMP-13 in brain tissue lysates from virologically suppressed HIV-infected individuals. In preliminary studies, MMP-13 can efficiently cleaves PNN components. Published work has linked MMP-13 expression to HIV infection, and also shown reduced PNN integrity in the background HIV associated cognitive dysfunction (HAND). Importantly, however, causes and potentially critical neurophysiological consequences of PNN disruption in the setting of HAND have not been well examined. In the present application, we plan to test the hypothesis that HIV relevant stimuli including Tat can stimulate MMP-dependent PNN processing in vitro and in vivo, with consequent effects on hippocampal PV activity, neuronal population dynamics and memory consolidation. !

由于强烈的兴奋性输入，可靠的GABA释放和快速的激发，小白蛋白表达(PV) 神经元被认为是同步网络事件的关键起搏器。PV神经元也代表被周围神经网络包裹的主要GABA能神经元群体 (PNN)，一种晶格状的细胞外基质，被认为定位谷氨酸能输入。PNN的中断与光伏兴奋性的降低有关。重要的是，光伏兴奋性缺陷会影响同步网络事件对注意力和长期记忆巩固都至关重要。为了支持…… 这一点，最近的研究表明，减少谷氨酸能输入到海马PV细胞，通过敲除PV选择性谷氨酸受体或减少突触前谷氨酸能神经支配，是与尖锐波纹(SWR)密度的增加和长期记忆巩固的缺陷有关。 PNN的加工是通过特定的蛋白水解酶的作用进行的。而“a”中的金属蛋白酶去整合素和金属蛋白酶与凝血酶反应蛋白基序和分泌型基质金属蛋白酶家族成员可以裂解特定的PNN成分，后者可能是在人类免疫缺陷病毒(HIV)感染的背景下，这一点尤为重要。可溶性MMPs 由神经元和小胶质细胞表达，并已知可消化PNN成分，包括聚集素和短发女郎。此外，虽然在猿猴的星形胶质细胞中没有检测到ADAMTS蛋白的表达在免疫缺陷病毒(SIV)模型中，PNN降解的MMPs是由星形胶质细胞高表达的，其中大脑中有大量的细胞类型。此外，在小鼠脑损伤模型中，选择性抑制基质金属蛋白酶减少PNN重塑。此前已经证明，人类HIV编码的TAT蛋白可以增加 MMP9的表达和/或细胞释放，它是PNN加工的有效调节剂。Tat蛋白是可在接受联合抗逆转录病毒治疗(CART)的个人的脑脊液中检测到。在……里面包括在这里的新的初步数据，我们表明TAT显著增加从星形胶质细胞。此外，我们在病毒学抑制的脑组织裂解物中看到了活性形式的基质金属蛋白酶-13 感染艾滋病毒的人。在初步研究中，基质金属蛋白酶-13可以有效地切割PNN组分。已发表的研究将基质金属蛋白酶-13的表达与艾滋病毒感染联系起来，并显示PNN减少诚信背景下的HIV相关认知功能障碍(手)。然而，重要的是，导致而在手部环境中PNN中断的潜在关键神经生理学后果尚未被仔细检查过了。在目前的应用中，我们计划测试艾滋病毒相关刺激的假设加入TAT可在体外和体内刺激依赖于基质金属蛋白酶的PNN的加工，从而产生相应的效应对海马PV活动、神经元种群动力学和记忆巩固的影响。好了！