Laboratory of Neuroscience, Department of Biophysics, Wroclaw Medical University, Chalubinskiego 3, 50368, Wroclaw, Poland.
Hippocampus. 2014 Feb;24(2):135-53. doi: 10.1002/hipo.22205. Epub 2013 Oct 15.
Matrix metalloproteases (MMP) play a pivotal role in long-term synaptic plasticity, learning, and memory. The roles of different MMP subtypes are emerging, but the proteolytic activity of certain MMPs was shown to support these processes through the structural and functional modification of hippocampal Schaeffer collateral and mossy fiber (MF) synapses. However, certain patterns of synaptic activity are additionally associated with non-synaptic changes, such as the scaling of neuronal excitability. However, the extent to which MMPs affect this process remains unknown. We determined whether MMP activity interferes with excitatory post-synaptic potential EPSP-to-spike (E-S) coupling under conditions of varying synaptic activity. We evoked short- and long-term synaptic plasticity at associational/commissural (A/C) synapses of CA3 pyramidal neurons and simultaneously recorded population spikes (PSs) and EPSPs in acute rat (P30-60) brain slices in the presence of various MMP inhibitors. We found that MMP inhibition significantly reduced E-S coupling and shortened the PS latency associated with 4× 100 Hz stimulation or paired burst activity of MF-CA3 and A/C synapses. Moreover, MMP inhibition interfered with the scaling of amplitude of measured signals during high-frequency trains, thus affecting the induction of long-term potentiation (LTP). The inhibition of L-type voltage-gated calcium channels with 20 µM nifedipine or GABA-A receptors with 1-30 µM picrotoxin did not occlude the effects of MMP inhibitors. However, MMP inhibition significantly reduced the LTP of NMDA receptor-mediated EPSPs. Finally, the analysis of LTP saturation with multiple single (1× 100 Hz) or packed (4× 100 Hz) trains indicated that MMPs support E-S coupling evoked by selected synaptic activity patterns and set the ceiling for tetanically evoked E-S LTP. In conclusion, the activity of MMPs, particularly MMP-3, regulated the magnitude of EPSPs and spike plasticity in the CA3 network and may affect information processing. Our data provide a novel link between MMP activity and neural excitability. Therefore, by limiting the number of firing neurons, MMP may functionally act beyond the synapse.
基质金属蛋白酶 (MMP) 在长期突触可塑性、学习和记忆中发挥关键作用。不同 MMP 亚型的作用正在显现，但某些 MMP 的蛋白水解活性被证明通过海马沙斐尔侧支和苔藓纤维 (MF) 突触的结构和功能修饰来支持这些过程。然而，某些突触活动模式还与非突触变化相关，例如神经元兴奋性的缩放。然而，MMP 对这个过程的影响程度尚不清楚。我们确定 MMP 活性是否会干扰在不同突触活动条件下兴奋性突触后电位 EPSP 到尖峰 (E-S) 偶联。我们在急性大鼠 (P30-60) 脑切片中诱发联合/联络 (A/C) 突触的短期和长期突触可塑性，同时记录群体峰 (PS) 和 EPSP，在各种 MMP 抑制剂存在下。我们发现，MMP 抑制显著降低了 E-S 偶联，并缩短了与 MF-CA3 和 A/C 突触的 4×100 Hz 刺激或成对爆发活动相关的 PS 潜伏期。此外，MMP 抑制干扰了高频列车期间测量信号幅度的缩放，从而影响了长时程增强 (LTP) 的诱导。用 20µM 硝苯地平抑制 L 型电压门控钙通道或用 1-30µM 印防己毒素抑制 GABA-A 受体并不能阻断 MMP 抑制剂的作用。然而，MMP 抑制显著降低了 NMDA 受体介导的 EPSP 的 LTP。最后，用多个单 (1×100 Hz) 或成组 (4×100 Hz) 列车分析 LTP 饱和表明，MMP 支持由选定的突触活动模式引发的 E-S 偶联，并为强直诱发的 E-S LTP 设置上限。总之，MMP 的活性，特别是 MMP-3，调节 CA3 网络中 EPSP 和尖峰可塑性的幅度，并可能影响信息处理。我们的数据为 MMP 活性和神经兴奋性之间提供了新的联系。因此，通过限制发射神经元的数量，MMP 可能在突触之外发挥功能。
