The Nuclear Calcium Signaling Target, Activating Transcription Factor 3 (ATF3), Protects against Dendrotoxicity and Facilitates the Recovery of Synaptic Transmission after an Excitotoxic Insult*
The Nuclear Calcium Signaling Target, Activating Transcription Factor 3 (ATF3), Protects against Dendrotoxicity and Facilitates the Recovery of Synaptic Transmission after an Excitotoxic Insult*
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DOI：
10.1074/jbc.m113.502914
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发表时间：
2014-04-04
影响因子：
4.8
通讯作者：
Bading, Hilmar
中科院分区：
文献类型：
--
作者：
Ahlgren, Hanna;Bas-Orth, Carlos;Bading, Hilmar
背景：受损神经元可见树突状突起，表现为树突局灶性肿胀。结果：兴奋性损伤后突触活性的增加和ATF3的过度表达减少了树突状珠状突起。结论：ATF3过表达可促进兴奋性损伤后神经网络功能的恢复。意义：基于ATF3的树突保护促进神经元损伤后的功能恢复。树突局灶性肿胀(树突珠)是神经元损伤和树突状毒性的早期形态特征。它们与包括脑缺血在内的各种病理条件有关，并导致突触传递和神经网络功能的急性中断，从而导致随后的神经元死亡。在这里，我们表明，在兴奋性毒性损伤之前增加的突触活性以转录依赖的方式保护树突状珠子不受影响。激活转录因子3(ATF3)是一种核钙调节基因，也是获得性神经保护核心基因计划的成员，表达ATF3可以保护树突状细胞免受珠状突起的侵袭。相反，ATF3的敲除会加剧树枝状珠子的形成。微电极阵列记录对神经元网络功能的评估表明，在染毒浓度NMDA后48h内，表达ATF3的海马神经元能够恢复其功能性突触传递的能力并参与连贯的神经元网络活动。因此，除了减轻细胞死亡，突触活性和ATF3的表达使海马神经元对急性树突状细胞毒性和突触丢失具有更强的抵抗力。树突状细胞保护可促进兴奋性损伤后神经网络功能的恢复。
Background: Injured neurons display dendritic beadings, which represent focal swellings of dendrites. Results: Increased synaptic activity and overexpression of ATF3 reduce dendritic beading after an excitotoxic insult. Conclusion: ATF3 overexpression facilitates recovery of neuronal network function after an excitotoxic insult. Significance: ATF3-based dendroprotection promotes functional recovery after neuronal injury.The focal swellings of dendrites (dendritic beading) are an early morphological hallmark of neuronal injury and dendrotoxicity. They are associated with a variety of pathological conditions, including brain ischemia, and cause an acute disruption of synaptic transmission and neuronal network function, which contribute to subsequent neuronal death. Here, we show that increased synaptic activity prior to excitotoxic injury protects, in a transcription-dependent manner, against dendritic beading. Expression of activating transcription factor 3 (ATF3), a nuclear calcium-regulated gene and member of the core gene program for acquired neuroprotection, can protect against dendritic beading. Conversely, knockdown of ATF3 exacerbates dendritic beading. Assessment of neuronal network functions using microelectrode array recordings revealed that hippocampal neurons expressing ATF3 were able to regain their ability for functional synaptic transmission and to participate in coherent neuronal network activity within 48 h after exposure to toxic concentrations of NMDA. Thus, in addition to attenuating cell death, synaptic activity and expression of ATF3 render hippocampal neurons more resistant to acute dendrotoxicity and loss of synapses. Dendroprotection can enhance recovery of neuronal network functions after excitotoxic insults.