Department of Neuroscience, Center for Neurovirology and Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania.
J Cell Physiol. 2018 Dec;233(12):9299-9311. doi: 10.1002/jcp.26322. Epub 2018 Jun 22.
HIV-associated neurocognitive disorders affecting greater than 30% of patients are caused by HIV-1 infection of the CNS, and in part, include neurotoxic effects of the viral transactivator of transcription, Tat protein. In addition to increasing the risk for becoming HIV infected, cocaine abuse enhances the neuropathogenic impacts of HIV-1. To investigate the outcome of Tat and cocaine interference in the hippocampal neuronal network, cross-rank-corrlation was employed to develop a systematic framework to assess hippocampal neurons behavior cultured on multielectrode arrays. Tat and cocaine differentially disturbed neuronal spiking rates, amplitude, synchronous activity, and oscillations within the hippocampal neuronal network via potentiation of inhibitory neurotransmission. The Tat-mediated impairment of neuronal spiking was reversible by removal of Tat, which restored neuronal activity. The presence of astrocytes co-cultured with neuronal networks diminished the effects of Tat and cocaine on neuron function suggesting a role for astrocytes in stabilizing neuronal behavior and increasing neuronal spontaneous activities such as bursting amplitude, frequency, and wave propagation rate. Taken together, our studies indicate that the HIV protein Tat and cocaine impair hippocampal neuronal network functioning and that the presence of astrocytes alleviates network dysfunction pointing to a newly discovered pathway through which ionic homeostasis is maintained by neuron-glial crosstalk in the CNS.
HIV 相关的神经认知障碍影响超过 30%的患者，是由 HIV-1 感染中枢神经系统引起的，部分原因包括病毒转录激活物 Tat 蛋白的神经毒性作用。除了增加感染 HIV 的风险外，可卡因滥用还增强了 HIV-1 的神经致病作用。为了研究 Tat 和可卡因对海马神经元网络的干扰结果，我们采用交叉秩相关分析来开发一种系统的框架，以评估在多电极阵列上培养的海马神经元的行为。Tat 和可卡因通过增强抑制性神经传递，对神经元的放电率、振幅、同步活动和海马神经元网络中的振荡产生差异干扰。通过去除 Tat，Tat 介导的神经元放电损伤是可逆的，恢复了神经元的活性。星形胶质细胞与神经元网络共培养的存在，减轻了 Tat 和可卡因对神经元功能的影响，这表明星形胶质细胞在稳定神经元行为和增加神经元自发性活动（如爆发振幅、频率和波传播率）方面发挥作用。总之，我们的研究表明，HIV 蛋白 Tat 和可卡因会损害海马神经元网络的功能，而星形胶质细胞的存在减轻了网络功能障碍，这表明通过神经元-神经胶质细胞的串扰来维持中枢神经系统离子稳态的新途径。
