Lynch G
University of California, Irvine, California 92697-3800, USA.
Neurobiol Learn Mem. 1998 Jul-Sep;70(1-2):82-100. doi: 10.1006/nlme.1998.3840.
Efforts to characterize long-term potentiation (LTP) and to identify its substrates have led to the discovery of novel synaptic chemistries, computational algorithms, and, most recently, pharmacologies. Progress has also been made in using LTP to develop a "standard model" of how unusual, but physiologically plausible, levels of afferent activity create lasting changes in the operating characteristics of synapses in the cortical telencephalon. Hypotheses of this type typically distinguish induction, expression, and consolidation stages in the formation of LTP. Induction involves a sequence consisting of theta-type rhythmic activity, suppression of inhibitory currents, intense synaptic depolarization, NMDA receptor activation, and calcium influx into dendritic spines. Calcium-dependent lipases, kinases, and proteases have been implicated in LTP induction. Regarding the last group, it has been recently reported that theta pattern stimulation activates calpain and that translational suppression of the protease blocks potentiation. It is thus likely that proteolysis is readily driven by synaptic activity and contributes to structural reorganization. LTP does not interact with treatments that affect transmitter release, has a markedly differential effect on the currents mediated by colocalized AMPA vs NMDA synaptic receptors, changes the waveform of the synaptic current, modifies the effects of drugs that modulate AMPA receptors, and is sensitive to the subunit composition of those receptors. These results indicate that LTP is expressed by changes in AMPA receptor operations. LTP is accompanied by modifications in the anatomy of synapses and spines, something which accounts for its extreme duration (weeks). As with various types of memory, LTP requires about 30 min to consolidate (become resistant to disruption). Consolidation involves adhesion chemistries and, in particular, activation of integrins, a class of transmembrane receptors that control morphology in numerous cell types. Platelet activating factor and adenosine may contribute to consolidation by regulating the engagement of latent integrins. How consolidation stabilizes LTP expression is a topic of intense investigation but probably involves modifications to one or more of the following: membrane environment of AMPA receptors; access of regulatory proteins (e.g., kinases, proteases) to the receptors; receptor clustering; and space available for receptor insertion. Attempts to enhance LTP have focused on the induction phase and resulted in a class of centrally active drugs ("ampakines") that positively modulate AMPA receptors. These compounds promote LTP in vivo and improve the encoding of variety of memory types in animals. Positive results have also been obtained in preliminary studies with humans.
对长时程增强（LTP）进行特征描述并确定其作用底物的努力，已促成了新型突触化学、计算算法以及最近的药理学的发现。在利用LTP建立一个“标准模型”方面也取得了进展，该模型用于解释异常但生理上合理的传入活动水平如何在大脑皮质端脑的突触操作特性中产生持久变化。这类假说通常区分LTP形成过程中的诱导、表达和巩固阶段。诱导过程涉及一个序列，包括θ型节律活动、抑制性电流的抑制、强烈的突触去极化、NMDA受体激活以及钙离子流入树突棘。钙依赖性脂肪酶、激酶和蛋白酶与LTP诱导有关。关于最后一组，最近有报道称θ模式刺激激活钙蛋白酶，并且该蛋白酶的翻译抑制会阻断增强作用。因此，蛋白水解很可能容易由突触活动驱动，并有助于结构重组。LTP与影响递质释放的处理方式不相互作用，对共定位的AMPA与NMDA突触受体介导的电流有明显不同的影响，改变突触电流的波形，改变调节AMPA受体的药物的作用，并且对这些受体的亚基组成敏感。这些结果表明LTP是通过AMPA受体操作的变化来表达的。LTP伴随着突触和树突棘解剖结构的改变，这解释了其极长的持续时间（数周）。与各种类型的记忆一样，LTP需要约30分钟来巩固（变得抗干扰）。巩固涉及黏附化学，特别是整合素的激活，整合素是一类跨膜受体，可控制多种细胞类型的形态。血小板活化因子和腺苷可能通过调节潜在整合素的结合来促进巩固。巩固如何稳定LTP表达是一个深入研究的课题，但可能涉及对以下一个或多个方面的修饰：AMPA受体的膜环境；调节蛋白（如激酶、蛋白酶）与受体的接触；受体聚集；以及受体插入可用的空间。增强LTP的尝试主要集中在诱导阶段，并产生了一类中枢活性药物（“安帕金”），它们能正向调节AMPA受体。这些化合物在体内促进LTP，并改善动物中各种记忆类型的编码。在对人类的初步研究中也获得了阳性结果。
