Anderson E R, Boyle J, Zink W E, Persidsky Y, Gendelman H E, Xiong H
Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5215, USA.
Neuroscience. 2003;118(2):359-69. doi: 10.1016/s0306-4522(02)00925-9.
Alterations in hippocampal physiology affect cognition in human immunodeficiency virus type 1 (HIV-1)-associated dementia (HAD). The mechanism for how this occurs is not well understood. To address this, we investigated how changes in synaptic transmission and plasticity are affected by viral infection and macrophage activation using a severe combined immunodeficiency mouse model of human HIV-1 encephalitis (HIVE). HIVE was induced in mice by stereotactic injection of HIV-1-infected human monocyte-derived macrophages (MDM) into the striatum. Animals were sacrificed after 3, 7 and 15 days. Hippocampal slices were prepared from HIV-1, MDM- and sham-injected animals. Electrically evoked field excitatory postsynaptic potentials were recorded in the CA1 region of the hippocampus. Neuronal physiology was assessed by input-output and by long-term potentiation (LTP) assays. We observed that a higher stimulation intensity (mA) was required to induce a 1-mV response in the HIVE mice (0.32+/-0.06) compared with shams (0.17+/-0.01) at day 7. The stimulation intensities at day 15 were 0.44+/-0.07 and 0.23+/-0.05 in the HIVE and shams, respectively. An impairment of synaptic function was detected through measuring synaptic responses induced by stimuli with different intensities. Paired-pulse facilitation (PPF) showed deficits in HIVE mice at days 3, 7, and 15. At day 3, PPF ratios were 1.13+/-0.02 and 1.24+/-0.04 in HIVE and sham. The induction and maintenance of LTP was also impaired in HIVE mice. The average magnitude of LTP was 131.23+/-15.26% of basal in HIVE as compared with sham animals of 232.63+/-24.18%. MDM-injected mice showed an intermediate response. Taken together, the results show a range of neuronal synaptic transmission and plasticity changes in HIVE mice that may reflect the mechanisms of cognitive dysfunction in human HAD.
海马体生理机能的改变会影响1型人类免疫缺陷病毒（HIV-1）相关痴呆症（HAD）患者的认知能力。其发生机制尚不清楚。为了探究这一问题，我们使用人类HIV-1脑炎（HIVE）的严重联合免疫缺陷小鼠模型，研究了病毒感染和巨噬细胞激活如何影响突触传递和可塑性的变化。通过将感染HIV-1的人类单核细胞衍生巨噬细胞（MDM）立体定向注射到纹状体中，在小鼠体内诱导出HIVE。在3、7和15天后处死动物。从注射HIV-1、MDM和进行假注射的动物身上制备海马体切片。在海马体的CA1区域记录电诱发的场兴奋性突触后电位。通过输入-输出和长时程增强（LTP）试验评估神经元生理机能。我们观察到，在第7天时，与假注射组（0.17±0.01）相比，HIVE小鼠诱导产生1 mV反应所需的刺激强度（mA）更高（0.32±0.06）。在第15天时，HIVE组和假注射组的刺激强度分别为0.44±0.07和0.23±0.05。通过测量不同强度刺激诱导的突触反应，检测到突触功能受损。配对脉冲易化（PPF）在第3、7和15天时显示HIVE小鼠存在缺陷。在第3天时，HIVE组和假注射组的PPF比率分别为1.13±0.02和1.24±0.04。HIVE小鼠中LTP的诱导和维持也受到损害。与假注射动物（232.63±24.18%）相比，HIVE小鼠LTP的平均幅度为基础值的131.23±15.26%。注射MDM的小鼠表现出中间反应。综上所述，结果表明HIVE小鼠存在一系列神经元突触传递和可塑性变化，这可能反映了人类HAD认知功能障碍的机制。
