Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice.
Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice.
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DOI：
10.1016/j.biopsych.2012.09.026
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发表时间：
2013-03-01
影响因子：
10.6
通讯作者：
Hauser, Kurt F.
中科院分区：
文献类型：
--
作者：
Fitting, Sylvia;Ignatowska-Jankowska, Bogna M.;Bull, Cecilia;Skoff, Robert P.;Lichtman, Aron H.;Wise, Laura E.;Fox, Michael A.;Su, Jianmin;Medina, Alexandre E.;Krahe, Thomas E.;Knapp, Pamela E.;Guido, William;Hauser, Kurt F.
关键词：
人类免疫缺陷病毒（HIV）相关神经认知障碍（HAND），包括记忆功能障碍，仍然是HIV-1型（HIV-1）感染的主要临床表现。被感染的神经胶质细胞释放的病毒蛋白被认为是炎症和旁观者神经元损伤和死亡的主要触发因素，从而驱动HAND的关键症状。我们使用了gap驱动的多西环素（DOX）诱导的HIV-1 Tat（转录反激活因子）转基因小鼠模型，并使用形态学（高尔基银浸渍、免疫组织化学、TUNEL检测、突触蛋白标记、电子显微镜）、电生理（长期增强（LTP））和行为学（莫里斯水迷宫、恐惧调节）方法检测了海马锥体CA1神经元的结构-功能关系。这种诱导在溶酶体、自噬液泡和板层体等星形细胞中引起了各种不同的包涵体，这些包涵体通常存在于远端细胞质突起中。在锥体CA1神经元中，Tat诱导减少了顶端树突棘的数量，同时破坏了与抑制传递相关的突触蛋白（synaptotagmin 2和gephyrin）的分布，但树突病理最小，没有锥体神经元死亡的证据。对Schaffer侧枝/交联纤维- ca1突触兴奋性突触后场电位（fEPSP）的电生理评估显示，表达Tat的小鼠几乎完全抑制LTP。LTP的丧失与学习和记忆的中断同时发生。Tat在大脑中的表达导致突触生理学和行为的深刻功能变化，而这些变化仅伴随适度的结构变化和最小的病理变化。它可能通过引起破坏突触组织的分子变化来促进HAND，含有synaptotagmin 2的抑制性突触前末端显得特别脆弱。
Human immunodeficiency virus (HIV) associated neurocognitive disorders (HAND), including memory dysfunction, continue to be a major clinical manifestation of HIV type-1 (HIV-1) infection. Viral proteins released by infected glia are thought to be the principal triggers of inflammation and bystander neuronal injury and death, thereby driving key symptomatology of HAND. We used a GFAP-driven, doxycycline (DOX)-inducible HIV-1 Tat (transactivator of transcription) transgenic mouse model and examined structure-function relationships in hippocampal pyramidal CA1 neurons using morphologic (Golgi-silver impregnations, immunohistochemistry, TUNEL detection, synaptic protein markers, electron microscopy), electrophysiological (long-term potentiation (LTP)), and behavioral (Morris water maze, fear-conditioning) approaches. Tat induction caused a variety of different inclusions in astrocytes characteristic of lysosomes, autophagic vacuoles, and lamellar bodies, which were typically present within distal cytoplasmic processes. In pyramidal CA1 neurons, Tat induction reduced the number of apical dendritic spines, while disrupting the distribution of synaptic proteins (synaptotagmin 2 and gephyrin) associated with inhibitory transmission, but with minimal dendritic pathology and no evidence of pyramidal neuron death. Electrophysiological assessment of excitatory postsynaptic field potential (fEPSP) at Schaffer collateral/commissural fiber-CA1 synapses showed near total suppression of LTP in mice expressing Tat. The loss in LTP coincided with disruptions in learning and memory. Tat expression in the brain results in profound functional changes in synaptic physiology and in behavior that are accompanied by only modest structural changes and minimal pathology. Tat likely contributes to HAND by causing molecular changes that disrupt synaptic organization, with inhibitory presynaptic terminals containing synaptotagmin 2 appearing especially vulnerable.
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DOI：
10.1073/pnas.0611699104
发表时间：
2007-02-27
影响因子：
11.1
作者：
Eugenin, Eliseo A.;King, Jessie E.;Berman, Joan W.
通讯作者：
Berman, Joan W.
影响因子：
2.5
作者：
Fox, Michael A.;Sanes, Joshua R.
通讯作者：
Sanes, Joshua R.
影响因子：
3.3
作者：
Brailoiu, G. C.;Brailoiu, E.;Dun, N. J.
通讯作者：
Dun, N. J.
影响因子：
56.9
作者：
DREYER, EB;KAISER, PK;LIPTON, SA
通讯作者：
LIPTON, SA
影响因子：
2.9
作者：
Dayhoff, Judith E.
通讯作者：
Dayhoff, Judith E.