Huang Y Y, Bach M E, Lipp H P, Zhuo M, Wolfer D P, Hawkins R D, Schoonjans L, Kandel E R, Godfraind J M, Mulligan R, Collen D, Carmeliet P
Howard Hughes Medical Institute, Center for Neurobiology and Behavior, College of Physicians and Surgeons of Columbia University, New York, USA.
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8699-704. doi: 10.1073/pnas.93.16.8699.
The gene encoding tissue-type plasminogen activator (t-PA) is an immediate response gene, downstream from CREB-1 and other constitutively expressed transcription factors, which is induced in the hippocampus during the late phase of long-term potentiation (L-LTP). Mice in which the t-PA gene has been ablated (t-PA-/-) showed no gross anatomical, electrophysiological, sensory, or motor abnormalities but manifest a selective reduction in L-LTP in hippocampal slices in both the Schaffer collateral-CA1 and mossy fiber-CA3 pathways. t-PA-/- mice also exhibit reduced potentiation by cAMP analogs and D1/D5 agonists. By contrast, hippocampal-dependent learning and memory were not affected in these mice, whereas performance was impaired on two-way active avoidance, a striatum-dependent task. These results provide genetic evidence that t-PA is a downstream effector gene important for L-LTP and show that modest impairment of L-LTP in CA1 and CA3 does not result in hippocampus-dependent behavioral phenotypes.
编码组织型纤溶酶原激活剂（t-PA）的基因是一种即时反应基因，位于CREB-1和其他组成型表达的转录因子的下游，在长期增强（L-LTP）的晚期在海马体中被诱导。t-PA基因已被敲除的小鼠（t-PA-/-）没有表现出明显的解剖学、电生理学、感觉或运动异常，但在海马体切片中，在Schaffer侧支-CA1和苔藓纤维-CA3通路中，L-LTP均表现出选择性降低。t-PA-/-小鼠对cAMP类似物和D1/D5激动剂的增强作用也降低。相比之下，这些小鼠的海马体依赖性学习和记忆不受影响，而在双向主动回避任务（一种纹状体依赖性任务）中的表现受损。这些结果提供了遗传学证据，表明t-PA是对L-LTP很重要的下游效应基因，并表明CA1和CA3中L-LTP的适度损伤不会导致海马体依赖性行为表型。
