Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
Neuroscience. 2010 Mar 17;166(2):508-21. doi: 10.1016/j.neuroscience.2009.12.061. Epub 2010 Jan 4.
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 30 min 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 murine 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.
基质金属蛋白酶（MMPs）是一组锌依赖性内肽酶，可在神经元活动依赖性方式下释放或激活。虽然病理性升高的 MMPs 水平可能具有突触毒性，但生理上适当的 MMPs 水平可能反而增强突触传递。MMP 抑制剂可以阻断长时程增强（LTP），至少有一种家族成员可以影响树突棘体积的增加。虽然 MMP 影响这些变化的机制尚未完全阐明，但一种可能性是特定的突触细胞粘附分子的裂解起作用。在本研究中，我们研究了神经元活动刺激快速 MMP 依赖性细胞间粘附分子-5（ICAM-5）的能力，ICAM-5 是一种突触粘附分子，被认为抑制树突棘的成熟和增大。由于如果与 LTP 等过程相关，则这种裂解可能在数分钟内发生，因此我们将重点放在刺激后 30 分钟或更短的时间点上。我们表明，NMDA 可以刺激分离细胞培养中的皮质神经元中 ICAM-5 的快速脱落，并且用针对 MMP-3 和 MMP-9 的抑制剂预处理培养物可减少这种脱落，这些蛋白酶被认为影响突触可塑性。进一步的研究表明，MMP 介导的 ICAM-5 裂解发生在氨基酸 780 处，因此释放了大部分胞外结构域。由于 ICAM-5 的减少与与 LTP 相关的树突棘形态变化有关，我们还检查了 MMP 依赖性 ICAM-5 脱落是否在小鼠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，并且在用 MMP 抑制剂预处理切片时，LTP 和相关的 ICAM-5 脱落都会减少。这些发现表明，神经元活动与一种可能抑制树突棘增大的分子的脱落有关，并且 MMP 可以影响这种变化。虽然需要进一步的研究来确定特定的 ICAM-5 裂解在多大程度上有助于 MMP 依赖性 LTP，但我们的数据支持越来越多的文献表明，MMP 是突触可塑性的关键介质。
