Krucker T, Toggas S M, Mucke L, Siggins G R
Scripps Research Institute and AIDS Research Center, Department of Neuropharmacology, La Jolla, CA 92037, USA.
Neuroscience. 1998 Apr;83(3):691-700. doi: 10.1016/s0306-4522(97)00413-2.
The human immunodeficiency virus type-1 envelope glycoprotein gp120 is shed from the virus and from infected cells and thus can diffuse and interact with a variety of central nervous system cells. Transgenic mice constitutively expressing glial fibrillary acidic protein-driven gp120 from brain astrocytes display neuronal and glial changes resembling abnormalities in human immunodeficiency virus type-1-infected human brains. To assess the neurophysiology of these transgenic mice and determine whether gp120 expression impairs synaptic plasticity, we examined CA1 population excitatory postsynaptic potentials in hippocampal slices from transgenic mice and from non-transgenic controls, using a double-blind protocol. Compared with slices from non-transgenic littermate controls, slices from gp120 transgenic mice showed four significant alterations: (i) increased mean slopes of normalized population excitatory postsynaptic potentials; (ii) larger paired-pulse facilitation after induction of long-term potentiation at 50 ms interpulse intervals; (iii) markedly elevated short-term potentiation after 10 and 20 shocks at 100 Hz; and (iv) a significant reduction in the magnitude of CA1 long-term potentiation. In slices from transgenic mice expressing Escherichia coli beta-galactosidase from the same promoter, paired-pulse facilitation and long-term potentiation were normal. These results indicate that brain slice preparations from gp120 transgenic mice can be used to assess pathophysiological effects of gp120 on neuronal networks. Because short-term potentiation involves presynaptic mechanisms, our results suggest that gp120 expression in these mice enhances either presynaptic glutamate release or postsynaptic glutamate receptor function, or both. These changes could lead to increased Ca2+ influx, thereby contributing to neuronal dysfunction and injury. As long-term potentiation is a cellular model of learning and memory, our results may be relevant to memory (cognitive) impairments seen in patients with AIDS.
人类免疫缺陷病毒1型包膜糖蛋白gp120会从病毒及受感染细胞上脱落，因此能够扩散并与多种中枢神经系统细胞相互作用。由脑星形胶质细胞组成性表达胶质纤维酸性蛋白驱动的gp120的转基因小鼠，表现出类似于人类免疫缺陷病毒1型感染人脑异常的神经元和胶质细胞变化。为了评估这些转基因小鼠的神经生理学，并确定gp120的表达是否会损害突触可塑性，我们采用双盲方案，检测了转基因小鼠和非转基因对照小鼠海马切片中CA1群体兴奋性突触后电位。与非转基因同窝对照小鼠的切片相比，gp120转基因小鼠的切片出现了四个显著变化：（i）标准化群体兴奋性突触后电位的平均斜率增加；（ii）在50毫秒脉冲间隔诱导长时程增强后，配对脉冲易化增强；（iii）在100赫兹下给予10次和20次电击后，短时程增强明显升高；（iv）CA1长时程增强的幅度显著降低。在来自同一启动子表达大肠杆菌β-半乳糖苷酶的转基因小鼠的切片中，配对脉冲易化和长时程增强均正常。这些结果表明，gp120转基因小鼠的脑切片标本可用于评估gp120对神经元网络的病理生理作用。由于短时程增强涉及突触前机制，我们的结果表明，这些小鼠中gp120的表达增强了突触前谷氨酸释放或突触后谷氨酸受体功能，或两者兼有。这些变化可能导致Ca2+内流增加，从而导致神经元功能障碍和损伤。由于长时程增强是学习和记忆的细胞模型，我们的结果可能与艾滋病患者出现的记忆（认知）障碍有关。
