Modulation of Inhibitory Synapses by HIV-1 Proteins and Cannabinoids

HIV-1 蛋白和大麻素对抑制性突触的调节

• 批准号: 8452813
• 负责人: Nicholas Hargus
• 金额: $ 5.22万
• 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: 2013-01-08 至 2015-01-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8452813
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Back; Biological Assay; Biological Neural Networks; Brain region; Cannabinoids; Cell Death; Cells; Cessation of life; DLG4 gene; Data; Dementia; Drug Targeting; Equilibrium; Excitatory Synapse; Exposure to; Foundations; Genetic Transcription; Glean; Glycoproteins; Goals; Green Fluorescent Proteins; HIV Envelope Protein gp120; HIV-1; Hippocampus (Brain); Hour; Image; Impaired cognition; Infection; Inhibitory Synapse; Intervention; Knowledge; Laboratories; Lead; Life; Light; Maintenance; Mediating; Microglia; Monitor; Morphology; N-Methyl-D-Aspartate Receptors; Nerve Degeneration; Neurodegenerative Disorders; Neuronal Injury; Neurons; Neurotoxins; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Presynaptic Terminals; Process; Proteins; Recovery; Relative (related person); Research; Role; Scaffolding Protein; Stimulus; Symptoms; Synapses; Synaptic Transmission; Testing; Therapeutic; Trans-Activators; Viral; Work; base; cannabinoid receptor; coping; density; drug of abuse; gephyrin; improved; insight; macrophage; neurotoxic; postsynaptic; presynaptic; presynaptic density protein 95; prevent; public health relevance; repaired; research study; restoration; theories; therapy design

DESCRIPTION (provided by applicant): Alterations in dendritic morphology such as dendritic pruning and synapse loss precede cell death in many neurodegenerative disorders, including HIV-1 associated dementia (HAD). Cognitive decline in patients with HAD is closely correlated with loss of excitatory synaptic connections. Loss of excitatory synapses following exposure to proteins released by HIV-1-infected cells occurs prior to and via a mechanism distinct from that leading to cell death. Synapse loss is reversible. Thus, loss of excitatory synapses appears to be a mechanism to cope with excess excitatory input induced by HIV-1 proteins. Neuronal networks, however, are comprised of both excitatory and inhibitory synaptic connections, and the dynamic interaction between the two defines the overall excitability of the network. The relative influence of inhibitory synapses in contributing to cognitive decline in HAD remains unclear. The premise of this proposal is that a better understanding of how inhibitory synaptic connections change when neural networks are exposed to HIV-1 proteins will ultimately improve how we understand and treat HAD. The focus of this study is the inhibitory post-synaptic density and how inhibitory synaptic connections change following exposure to HIV-1 proteins. Preliminary studies demonstrated that inhibitory synapse numbers increase when neuronal cultures are exposed to HIV-1 proteins as opposed to the marked decrease of excitatory synapses, suggesting that inhibitory synapses may scale to counteract HIV-1- induced increases in network excitability. The goal of the proposed research is to build on this foundation by to determine factors that modulate HIV-1 protein-induced changes in inhibitory synapses, mechanisms underlying the restoration of inhibitory synapses following exposure to HIV-1 proteins, and the possible role of cannabinoids in modulating these changes. Effort will be centered on three inter-related Specific Aims: (1) Determine the relationship between HIV-1 neurotoxin-induced alterations in excitatory and inhibitory synaptic connections. The hypothesis that inhibitory synaptic connections increase to compensate for network over- excitation induced by exposure to HIV-1 proteins will be tested. (2) Examine the ability of inhibitory synapses to return to basal levels following exposure to HIV-1 proteins. The hypothesis that stimuli known to induce recovery of excitatory synapses following HIV-1-induced loss will restore inhibitory synapses back to basal levels will be tested. (3) Investigate the effects of cannabinoids on HIV-1 protein-induced alterations in inhibitory synapses. The hypothesis that activation of cannabinoid receptors will protect from HIV-1 protein- induced increases in inhibitory synapses will be tested. These specific aims will be carried out using live-cell confocal imaging to count postsynaptic densities, presynaptic syGCaMP2 imaging to assess network excitability, and pharmacology to determine the mechanism responsible. The insights gleaned from these studies will enhance our understanding of how inhibitory synapses respond to exposure to HIV-1 proteins, while offering new insights into possible pharmacotherapies targeting inhibitory synapses to treat HAD.

描述（由申请人提供）：树突状形态的改变，例如树突修剪和突触损失，先于许多神经退行性疾病（包括HIV-1相关痴呆症（HAD））的细胞死亡。患者患者的认知能力下降与兴奋性突触连接的丧失密切相关。暴露于HIV-1感染细胞释放的蛋白质后的兴奋性突触丧失发生在与导致细胞死亡的机制之前和通过不同的机制发生。突触损失是可逆的。因此，兴奋性突触的丧失似乎是应对HIV-1蛋白引起的过量兴奋性输入的机制。但是，神经元网络既由兴奋性和抑制性突触连接组成，并且两者之间的动态相互作用定义了网络的整体兴奋性。抑制性突触在导致认知下降的相对影响尚不清楚。该提案的前提是，当神经网络暴露于HIV-1蛋白质时，对抑制性突触连接的改变有了更好的理解，最终将改善我们的理解和治疗方式。这项研究的重点是暴露于HIV-1蛋白后的抑制性突触后密度以及抑制性突触连接如何变化。初步研究表明，当神经元培养物暴露于HIV-1蛋白而不是明显的兴奋性突触下降时，抑制性突触数量增加，这表明抑制性突触可能会扩展以抵消HIV-1-诱导的HIV-1-诱导的网络兴奋性增加。拟议的研究的目的是建立在这个基础的基础上 通过确定调节HIV-1蛋白诱导的抑制性突触变化的因素，暴露于HIV-1蛋白后恢复抑制性突触的机制以及大麻素在调节这些变化中的可能作用。努力将集中在三个相互关联的特定目的上：（1）确定HIV-1神经毒素诱导的兴奋性和抑制性突触连接的改变之间的关系。将测试抑制性突触连接增加以补偿暴露于HIV-1蛋白引起的网络过度激发的假设。 （2）检查暴露于HIV-1蛋白后抑制性突触返回基础水平的能力。 HIV-1诱导的损失后已知刺激突触恢复的刺激的假设将恢复抑制性突触回到基础水平。 （3）研究大麻素对HIV-1蛋白诱导的抑制性突触改变的影响。将测试大麻素受体的激活将保护HIV-1蛋白诱导的抑制性突触增加的假设。这些具体目标将使用活细胞共聚焦成像进行，以计算突触后密度，突触前SYGCAMP2成像以评估网络兴奋性和药理，以确定负责的机制。从这些研究中收集的见解将增强我们对抑制性突触如何对暴露于HIV-1蛋白的反应的理解，同时为靶向抑制性突触的可能药物治疗提供新的见解。