Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, C/ Casanova, 143 08036, Barcelona, Catalonia, Spain.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Catalonia, Spain.
Mol Neurobiol. 2019 Feb;56(2):1475-1487. doi: 10.1007/s12035-018-1170-1. Epub 2018 Jun 12.
Striatal-enriched protein tyrosine phosphatase (STEP) modulates key signaling molecules involved in synaptic plasticity and neuronal function. It is postulated that STEP opposes the development of long-term potentiation (LTP) and that it exerts a restraint on long-term memory (LTM). Here, we examined whether STEP levels are regulated during hippocampal LTP and after training in hippocampal-dependent tasks. We found that after inducing LTP by high frequency stimulation or theta-burst stimulation STEP levels were significantly reduced, with a concomitant increase of STEP levels, a product of calpain cleavage. Importantly, inhibition of STEP with TC-2153 improved LTP in hippocampal slices. Moreover, we observed that after training in the passive avoidance and the T-maze spontaneous alternation task, hippocampal STEP levels were significantly reduced, but STEP levels were unchanged. Yet, hippocampal BDNF content and TrkB levels were increased in trained mice, and it is known that BDNF promotes STEP degradation through the proteasome. Accordingly, hippocampal pTrkB, pPLCγ, and protein ubiquitination levels were increased in T-SAT trained mice. Remarkably, injection of the TrkB antagonist ANA-12 (2 mg/Kg, but not 0.5 mg/Kg) elicited LTM deficits and promoted STEP accumulation in the hippocampus. Also, STEP knockout mice outperformed wild-type animals in an age- and test-dependent manner. Summarizing, STEP undergoes proteolytic degradation in conditions leading to synaptic strengthening and memory formation, thus highlighting its role as a molecular constrain, which is removed to enable the activation of pathways important for plasticity processes.
纹状体丰富的蛋白酪氨酸磷酸酶（STEP）调节参与突触可塑性和神经元功能的关键信号分子。据推测，STEP 反对长时程增强（LTP）的发展，并且对长时记忆（LTM）施加限制。在这里，我们检查了 STEP 水平是否在海马体 LTP 期间以及在海马体依赖任务的训练后进行调节。我们发现，通过高频刺激或θ爆发刺激诱导 LTP 后，STEP 水平显着降低，同时 STEP 水平增加，这是钙蛋白酶切割的产物。重要的是，用 TC-2153 抑制 STEP 可改善海马切片中的 LTP。此外，我们观察到在被动回避和 T 迷宫自发交替任务中进行训练后，海马体 STEP 水平显着降低，但 STEP 水平不变。然而，在训练后的小鼠中海马 BDNF 含量和 TrkB 水平增加，并且已知 BDNF 通过蛋白酶体促进 STEP 降解。因此，在 T-SAT 训练的小鼠中海马 pTrkB、pPLCγ 和蛋白质泛素化水平增加。值得注意的是，注射 TrkB 拮抗剂 ANA-12（2 mg/Kg，但不是 0.5 mg/Kg）会引起 LTM 缺陷，并促进海马体中 STEP 的积累。此外，在年龄和测试依赖性方面，STEP 敲除小鼠的表现优于野生型动物。总之，在导致突触增强和记忆形成的条件下，STEP 经历蛋白水解降解，从而突出了其作为分子限制的作用，这种限制被去除以激活对可塑性过程重要的途径。
