Microtubule disruption, not calpain-dependent loss of MAP2, contributes to enduring NMDA-induced dendritic dysfunction in acute hippocampal slices
Microtubule disruption, not calpain-dependent loss of MAP2, contributes to enduring NMDA-induced dendritic dysfunction in acute hippocampal slices
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DOI：
10.1016/j.expneurol.2006.06.010
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发表时间：
2006-12-01
影响因子：
5.3
通讯作者：
Shuttleworth, C. William
中科院分区：
文献类型：
--
作者：
Hoskison, M. M.;Shuttleworth, C. William
短暂接触兴奋性毒性激动剂会导致神经元树突中微管相关蛋白 MAP2 的大量损失，并在体细胞中积累。 MAP2 丢失的一个可能机制是过量的树突 Ca2+ 负载激活钙依赖性蛋白酶钙蛋白酶。本研究检查了急性制备的海马切片的 CA1 区域中 MAP2 重新分布和突触功效丧失的机制。短暂的 NMDA 暴露会导致突触后电位持续而深刻的抑制，以及树突区室中 MAP2 的丢失。当 Ca2+ 在 NMDA 暴露期间被去除时，突触电位在 NMDA 冲洗期间显着恢复，并且 MAP2 损失减少。用 MDL 28,170 (20 μM) 抑制钙蛋白酶并不能阻止突触电位的丧失，也不能减弱 MAP2 最初聚集成不规则树突肿胀的过程。然而，MDL 28,170 确实减少了异常树突聚集导致的后续 MAP2 损失。将切片预先暴露于紫杉醇 (100 nM) 中，可有效防止 NMDA 暴露后的微管解聚，以及 MAP2 的解体和顶端树突的损失。用紫杉醇处理的切片在短暂的 NMDA 刺激后也表现出突触电位的显着恢复。这些结果表明，顶端树突中 MAP2 的维持定位与短暂 NMDA 暴露后突触后电位的恢复之间存在密切的对应关系。此外，钙蛋白酶活性似乎不是通过 MAP2 蛋白水解对微管结构进行初始破坏，而是可能有助于微管解聚后观察到的不规则聚集的 MAP2 的降解。 (c) 2006 Elsevier Inc. 保留所有权利。
Brief exposure to excitotoxic agonists can result in substantial loss of the microtubule-associated protein MAP2 from neuronal dendrites, and accumulation in somata. A possible mechanism underling MAP2 loss is the activation of the calcium-dependent protease calpain by excessive dendritic Ca2+-loading. The present study examined mechanisms of MAP2 redistribution and loss of synaptic efficacy in the CA1 region of acutely prepared hippocampal slices. Brief NMDA exposure resulted in persistent and profound inhibition of postsynaptic potentials, and loss of MAP2 from dendritic compartments. When Ca2+ was removed during NMDA exposure, synaptic potentials recovered significantly during NMDA washout, and MAP2 loss was reduced. Calpain inhibition with MDL 28,170 (20 mu M) did not prevent the loss of synaptic potentials, nor did it attenuate the initial aggregation of MAP2 into irregular dendritic swellings. However MDL 28,170 did reduce subsequent MAP2 loss from abnormal dendritic aggregates. Pre-exposure of slices to taxol (100 nM) effectively prevented microtubule depolymerization following NMDA exposure, as well as MAP2 disorganization and loss from apical dendrites. Slices treated with taxol also exhibited substantial recovery of synaptic potentials after transient NMDA stimulus. These results demonstrate a close correspondence between the maintained localization of MAP2 in apical dendrites and the recovery of postsynaptic potentials following transient NMDA exposure. In addition, it appears that rather than underlying the initial disruption of microtubule structure via MAP2 proteolysis, calpain activity instead may contribute to the degradation of irregularly aggregated MAP2 observed following microtubule depolymerization. (c) 2006 Elsevier Inc. All rights reserved.