Stäubli U, Chun D, Lynch G
Center for Neural Science, New York University, New York, New York 10003, USA.
J Neurosci. 1998 May 1;18(9):3460-9. doi: 10.1523/JNEUROSCI.18-09-03460.1998.
The integrin antagonist Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP) was applied by local ejection to one of two recording sites in hippocampal slices at various times before and after long-term potentiation (LTP) was induced at both sites with theta burst stimulation. Applications 10 min before, immediately after, and 10 min after induction caused LTP at the experimental site to decay steadily relative to that at the within-slice control site. However, application at 25 min or more after induction had no detectable effect on potentiation. Similar results were obtained when the integrin antagonist was perfused into the slice rather than applied locally. The time period after induction during which GRGDSP interfered with LTP consolidation corresponds to that during which LTP is susceptible to reversal by low-frequency afferent stimulation and newly formed memories are vulnerable to various disruptive treatments. Comparable experiments using a peptide that blocks an extracellular binding site of neural cell adhesion molecules (NCAMs) did not yield time-dependent reversal of LTP; i.e., an antagonist that interacts with the fourth immunoglobulin-like domain reduced LTP when applied before induction but not afterward. Moreover, LTP formation occurred normally in the presence of an antibody against the fibronectin repeat domain of NCAM. These results suggest that integrin activation and signaling occurring over several minutes after LTP induction are necessary for stabilizing synaptic potentiation and by inference may be required for the conversion of new memories into a not readily disrupted state.
整合素拮抗剂甘氨酸 - 精氨酸 - 甘氨酸 - 天冬氨酸 - 丝氨酸 - 脯氨酸（GRGDSP）在通过θ波爆发刺激在两个记录位点诱导长时程增强（LTP）之前和之后的不同时间，通过局部注射施加到海马切片的两个记录位点之一。在诱导前10分钟、诱导后立即以及诱导后10分钟进行注射，相对于切片内对照位点，实验位点的LTP会稳定衰减。然而，在诱导后25分钟或更长时间进行注射对增强没有可检测到的影响。当将整合素拮抗剂灌注到切片中而不是局部应用时，也获得了类似的结果。GRGDSP干扰LTP巩固的诱导后时间段，与LTP易受低频传入刺激逆转以及新形成的记忆易受各种破坏处理影响的时间段相对应。使用阻断神经细胞粘附分子（NCAMs）细胞外结合位点的肽进行的类似实验，未产生LTP的时间依赖性逆转；即，与第四免疫球蛋白样结构域相互作用的拮抗剂在诱导前应用时会降低LTP，但在诱导后则不会。此外，在存在针对NCAM纤连蛋白重复结构域的抗体的情况下，LTP形成正常发生。这些结果表明，LTP诱导后几分钟内发生的整合素激活和信号传导对于稳定突触增强是必要的，并且由此推断，可能是将新记忆转化为不易被破坏状态所必需的。
