Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation.
Matrix metalloproteinase-dependent shedding of intercellular adhesion molecule-5 occurs with long-term potentiation.
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基质金属蛋白酶依赖性酶间粘附分子-5的脱落发生长期增强。
DOI：
10.1016/j.neuroscience.2009.12.061
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发表时间：
2010-03-17
期刊：
影响因子：
3.3
通讯作者：
Lim, S. T.
中科院分区：
文献类型：
--
作者：
Conant, K.;Wang, Y.;Szklarczyk, A.;Dudak, A.;Mattson, M. P.;Lim, S. T.
基质金属蛋白酶（MMP）是一个锌依赖性内肽酶家族，可以以神经元活性依赖的方式释放或激活。尽管病理学上升高的MMP水平可能是突触毒性的，但生理学上适当水平的MMP反而可以增强突触传递。MMP抑制剂可以阻断长时程增强（LTP），并且至少一个家族成员可以影响树突棘体积的增加。虽然MMPs影响这些变化的机制还不完全清楚，但一种可能性是特异性突触细胞粘附分子的切割起作用。在本研究中，我们研究了神经元活性刺激细胞间粘附分子-5（ICAM-5）（一种被认为抑制树突棘成熟和扩大的突触粘附分子）快速MMP依赖性脱落的能力。由于这种分裂可能会发生在几分钟内，如果它是相关的过程，如LTP，我们专注于刺激后的时间点为30分钟或less. We表明，NMDA可以刺激快速脱落的ICAM-5从皮质神经元在解离的细胞cultures和这种脱落是减少预处理的文化与抑制剂，目标MMP-3和-9，蛋白酶被认为会影响突触可塑性。另外的研究表明，MMP介导的ICAM-5的切割发生在氨基酸780处，从而释放胞外域的主要部分。由于ICAM-5的减少与LTP相关的树突棘形态学的变化有关，我们还研究了MMP依赖性ICAM-5脱落在海马切片的高频强直刺激后发生的可能性。结果表明，ICAM-5的脱落与LTP相关，并且当切片用MMP抑制剂预处理时，LTP和相关的ICAM-5脱落都减少。总之，这些发现表明，神经元活动与可能抑制树突棘扩大的分子的脱落有关，并且MMPs可以影响这种变化。虽然进一步的研究将是必要的，以确定在何种程度上的ICAM-5的裂解，特别是有助于MMP依赖性LTP，我们的数据支持一个新兴的机构的文献表明，MMP是突触可塑性的关键介质。
Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that can be released or activated in a neuronal activity dependent manner. Although pathologically elevated levels of MMPs may be synaptotoxic, physiologically appropriate levels of MMPs may instead enhance synaptic transmission. MMP inhibitors can block long term potentiation (LTP), and at least one family member can affect an increase in the volume of dendritic spines. While the mechanism by which MMPs affect these changes is not completely understood, one possibility is that the cleavage of specific synaptic cell adhesion molecules plays a role. In the present study, we have examined the ability of neuronal activity to stimulate rapid MMP dependent shedding of the intercellular adhesion molecule-5 (ICAM-5), a synaptic adhesion molecule that is thought to inhibit the maturation and enlargement of dendritic spines. Since such cleavage would likely occur within minutes if it were relevant to a process such as LTP, we focused on post stimulus time points of thirty minutes or less. We show that NMDA can stimulate rapid shedding of ICAM-5 from cortical neurons in dissociated cell cultures and that such shedding is diminished by pretreatment of cultures with inhibitors that target MMP-3 and -9, proteases thought to influence synaptic plasticity. Additional studies suggest that MMP mediated cleavage of ICAM-5 occurs at amino acid 780, so that the major portion of the ectodomain is released. Since reductions in ICAM-5 have been linked to changes in dendritic spine morphology that are associated with LTP, we also examined the possibility that MMP dependent ICAM-5 shedding occurs following high frequency tetanic stimulation of hippocampal slices. Results show that the shedding of ICAM-5 occurs in association with LTP, and that both LTP and the associated ICAM-5 shedding are reduced when slices are pretreated with an MMP inhibitor. Together, these findings suggest that neuronal activity is linked to the shedding of a molecule that may inhibit dendritic spine enlargement and that MMPs can affect this change. While further studies will be necessary to determine the extent to which cleavage of ICAM-5 in particular contributes to MMP dependent LTP, our data support an emerging body of literature suggesting that MMPs are critical mediators of synaptic plasticity.
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