Norris Erin H, Strickland Sidney
Laboratory of Neurobiology and Genetics, The Rockefeller University, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2007 Aug 14;104(33):13473-8. doi: 10.1073/pnas.0705848104. Epub 2007 Aug 2.
Contextual fear conditioning is regulated by the hippocampus, and NR2B, a subunit of the NMDA receptor (NR), is involved in this process. We show that acute stress modulates tissue plasminogen activator (tPA) activity in the hippocampus by inducing expression of its inhibitor, plasminogen activator inhibitor-1. Acute stress increases NR2B expression and ERK1/2 phosphorylation, a classical marker of postsynaptic plasticity, in the hippocampus. tPA forms a complex with NR2B and is necessary for binding NR2B to postsynaptic density-95, allowing for NR activation and membrane anchoring. Acute stress increases the interaction between NR2B and RACK-1, which is also dependent on tPA, further suggesting that tPA is an important factor in NMDA signaling and plasticity in the hippocampus. Finally, acutely stressed tPA(-/-) mice show a decrease in contextual fear conditioning compared with stressed WT mice. These results indicate that tPA is a key modulator in stabilizing the NR complex during stress and participates in changes in behavior and synaptic plasticity.
情境恐惧条件反射受海马体调节，NMDA受体（NR）的亚基NR2B参与此过程。我们发现，急性应激通过诱导组织纤溶酶原激活物（tPA）的抑制剂纤溶酶原激活物抑制剂-1的表达来调节海马体中的tPA活性。急性应激会增加海马体中NR2B的表达以及ERK1/2磷酸化，后者是突触后可塑性的经典标志物。tPA与NR2B形成复合物，是NR2B与突触后致密蛋白-95结合所必需的，从而实现NR的激活和膜锚定。急性应激会增加NR2B与RACK-1之间的相互作用，这也依赖于tPA，进一步表明tPA是海马体中NMDA信号传导和可塑性的重要因素。最后，与应激的野生型小鼠相比，急性应激的tPA基因敲除小鼠在情境恐惧条件反射方面表现出下降。这些结果表明，tPA是应激期间稳定NR复合物的关键调节因子，并参与行为和突触可塑性的变化。
