Abnormal Striatal Dopaminergic Synapses in National NeuroAIDS Tissue Consortium Subjects with HIV Encephalitis
Abnormal Striatal Dopaminergic Synapses in National NeuroAIDS Tissue Consortium Subjects with HIV Encephalitis
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DOI：
10.1007/s11481-006-9030-6
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发表时间：
2006-12-01
影响因子：
6.2
通讯作者：
Soukup, Vicki M.
中科院分区：
文献类型：
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作者：
Gelman, Benjamin B.;Spencer, Jeffrey A.;Soukup, Vicki M.
患有人类免疫缺陷病毒（HIV）/获得性免疫缺陷综合征（AIDS）的人具有与异常多巴胺能（DA能）突触传递相关的疾病重叠的神经问题，包括皮质下痴呆、运动减慢、精神病和药物成瘾。以前的研究表明，DA能紧张可能会减少艾滋病毒/艾滋病，但生化证实这一原则仍然缺乏。为此，本研究探讨了人类大脑标本中HIV感染和DA能突触传递之间的神经化学相互作用。DA能突触的蛋白质标记物的特点是在纹状体匀浆从个人与HIV脑炎（HIVE）和血清阴性对照从尸检队列的国家NeuroAIDS组织协会。HIVE患者纹状体DA能标记物异常。异常突触前标记物包括酪氨酸羟化酶（TH）蛋白减少和磷酸化TH减少。突触前多巴胺再摄取转运体（DAT）明显增加。突触后异常包括2型多巴胺受体（D2 R）减少和D3 R增加。相对于短同种型，选择性剪接的长同种型D2 R优先丢失。异常DA能突触蛋白与纹状体提取物中扩增的HIV Gag mRNA转录物显着相关。这些突触变化类似于DA能张力实验增加时发生的变化。DA能张力增加导致药物滥用的显著性提高，增加增加HIV传播风险的行为，并可能降低抗逆转录病毒药物治疗方案的依从性。
People with human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) have neurological problems that overlap with diseases associated with abnormal dopaminergic (DAergic) synaptic transmission, including subcortical dementia, motor slowing, psychosis, and drug addiction. Previous study has suggested that DAergic tone may be decreased in HIV/AIDS, but biochemical confirmation of that tenet is still lacking. To that end, this study addresses the neurochemical interaction between HIV infection and DAergic synaptic transmission in human brain specimens. Protein markers of DAergic synapses were characterized in homogenates of the corpus striatum from individuals with HIVencephalitis (HIVE) and seronegative controls from the autopsy cohort of the National NeuroAIDS Tissue Consortium. Striatal DAergic markers were abnormal in HIVE. Abnormal presynaptic markers included decreased tyrosine hydroxylase (TH) protein and decreased phosphorylated TH. The presynaptic dopamine reuptake transporter (DAT) was increased reciprocally. Postsynaptic abnormalities included decreased dopamine receptor type 2 (D2R) and increased D3R. There was preferential loss of the alternatively spliced long isoform of D2R relative to the short isoform. Abnormal DAergic synapse proteins were significantly correlated with the HIV Gag mRNA transcripts amplified in striatal extracts. These synaptic changes resemble shifts that occur when DAergic tone is increased experimentally. Increased DAergic tone leads to heightened salience for drugs of abuse, increases behaviors that increase the risk of HIV transmission, and might decrease compliance with antiretroviral medication regimens.