Pharmacological modulation of synapses and cognition during HIV-1 neurotoxicity

HIV-1神经毒性过程中突触和认知的药理学调节

• 批准号: 8650820
• 负责人: Stanley A Thayer
• 金额: $ 19万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8650820
• 关键词: AIDS neuropathy; Acquired Immunodeficiency Syndrome; Affect; Agonist; Animal Model; Animals; Antiemetics; Appetite Stimulants; Behavior; Biological Assay; Bipolar Disorder; CNR1 gene; CNR2 gene; Cannabinoids; Cell Death; Cells; Cognition; Cognitive; DLG4 gene; Detection; Disease; Drug usage; Exhibits; Exposure to; Foundations; Green Fluorescent Proteins; HIV Envelope Protein gp120; HIV Infections; HIV-1; Image; Imaging technology; Impaired cognition; Impairment; In Vitro; Lithium; Mediating; Microglia; Modeling; Monitor; Morphology; Mus; N-Methyl-D-Aspartate Receptors; Neurocognitive; Neurodegenerative Disorders; Neurologic; Neurons; Neurotoxins; Patients; Performance; Pharmaceutical Preparations; Process; Proteins; Recovery; Scaffolding Protein; Site; Structure; Synapses; Technology; Testing; Toxin; Transgenic Mice; arachidonyl-2-chloroethylamide; base; behavior test; cannabinoid receptor; cognitive change; cognitive function; cognitive recovery; density; drug development; drug of abuse; env Gene Products; ifenprodil; improved; improved functioning; in vivo; insight; mouse model; neurotoxicity; postsynaptic; prevent; promoter; public health relevance; release factor; research study; synaptogenesis; tat Protein

DESCRIPTION (provided by applicant): Changes in dendritic morphology such as dendritic pruning precede cell death in many neurodegenerative disorders, including HIV-1-associated neurocognitive disorders (HAND). Dendritic degeneration correlates with cognitive decline in HAND. A confocal imaging-based assay was developed to detect intact postsynaptic densities (PSDs) based on detection of clusters of the scaffolding protein PSD95 fused to green fluorescent protein (PSD95-GFP). In neuronal cultures, PSD95-GFP puncta were lost following exposure to factors released by HIV-1 infected cells including the HIV-1 proteins Tat and gp120. PSD loss induced by HIV-1 neurotoxins is reversible. This proposal will relate the loss and recovery of synapses to cognitive function in mouse models of neuroAIDS. In vivo multiphoton imaging will track PSD95-GFP puncta during expression of HIV-1 proteins and behavioral tests will monitor cognitive function. The first aim is to relate HIV-1 protein induced synapse loss and recovery to cognitive performance. Treatment with ifenprodil, an antagonist selective for NR2B-containing NMDA receptors, induced the recovery of synapses lost following in vitro exposure to the HIV-1 protein Tat. What remains unclear is whether synapses recover in vivo and if they do, whether cognitive function improves. Transgenic mice that express Tat under the control of an inducible promoter exhibit synaptic degeneration and cognitive decline following induction. The hypothesis that ifenprodil will evoke recovery of synapses lost in Tat-expressing animals and that synaptic recovery will correlate with improved cognitive function will be tested. Anticipated results may provide proof of the principle that drug-induced changes in synaptic number predict changes in cognitive function. The second aim is to determine the effects of cannabinoids, drugs given to AIDS patients clinically and widely used illicitly, on the synaptic and cognitive changes induced by HIV-1 proteins. Synapse loss and recovery is a dynamic process influenced by cannabinoids in vitro. The effects of cannabinoids on cognitive function in HIV-1 models are unknown. Agonists selective for cannabinoid receptor subtypes will be tested in transgenic mice expressing the HIV-1 proteins gp120 or Tat. The CB2 agonist JWH-133 is predicted to improve cognition in gp120- expressing mice. In contrast, the CB1 agonist arachidonyl-2'-chloroethylamide (ACEA) is predicted to impair ifenprodil-induced synapse recovery and limit cognitive improvement in Tat-expressing mice. If cannabinoids impair synaptic and cognitive recovery, this result would caution against recreational use of cannabinoids or their use as antiemetics and appetite stimulants in patients with HAND. In vivo multiphoton imaging has potentially broad applications for relating the effects of drugs on synaptic structure to their effects on behavior. This project will provide a foundation to guide th development of drugs to improve function in HAND patients and will identify sites where drugs of abuse might interact with the formation and loss of synapses.

描述（由申请人提供）：树突形态的变化（例如树突状修剪）先前在许多神经退行性疾病中的细胞死亡之前，包括HIV-1相关的神经认知疾病（HAND）。树突变性与手头认知下降相关。开发了一种基于共聚焦成像的测定方法，以检测基于融合到绿色荧光蛋白（PSD95-GFP）的脚手架蛋白PSD95的簇的簇检测到完整的突触后密度（PSD）。在神经元培养物中，暴露于HIV-1感染细胞（包括HIV-1蛋白Tat和gp120）的因素后，PSD95-GFP点丢失了。 HIV-1神经毒素诱导的PSD损失是可逆的。该建议将在神经辅助小鼠模型中将突触的损失和恢复与认知功能有关。体内多光子成像将在HIV-1蛋白表达期间跟踪PSD95-GFP点，行为测试将监测认知功能。第一个目的是将HIV-1蛋白诱导的突触丧失和恢复与认知表现联系起来。用Ifenprodil的治疗是一种对含NR2B NMDA受体的拮抗剂选择性的拮抗剂，诱导了在体外暴露于HIV-1蛋白TAT之后丧失的突触的恢复。尚不清楚的是，突触是否在体内恢复以及是否这样做，认知功能是否有所改善。在诱导型启动子控制下表达TAT的转基因小鼠在诱导后表现出突触变性和认知下降。 Ifenprodil将引起表达TAT动物中失去的突触的恢复，而突触恢复将与改善的认知功能相关的假设。预期的结果可能提供了这样的证据，证明了药物诱导的突触数变化预测认知功能的变化的原则。第二个目的是确定大麻素的作用，大麻素，临床和非法使用艾滋病患者的药物对HIV-1蛋白引起的突触和认知变化。突触丧失和恢复是一个动态过程，受大麻素在体外的影响。大麻素对HIV-1模型认知功能的影响尚不清楚。在表达HIV-1蛋白GP120或TAT的转基因小鼠中，将测试对大麻素受体亚型的激动剂选择性。预计CB2激动剂JWH-133可以改善GP120-表达小鼠的认知。相比之下，预测CB1激动剂Arachidonyl-2'-氯乙酰酰胺（ACEA）会损害Ifenprodil诱导的突触恢复并限制表达TAT的小鼠的认知改善。如果大麻素会损害突触和认知恢复，则该结果将警告不要娱乐性使用大麻素或用作手动患者的抗魔术和食欲刺激剂。体内多光子成像具有将药物对突触结构的影响与其对行为的影响联系起来的潜在广泛应用。该项目将为指导药物开发以改善手动患者的功能，并确定滥用药物可能与突触的形成和丧失相互作用的部位。