Kim Jeongyeon, Lee Sukwon, Park Kyungjoon, Hong Ingie, Song Beomjong, Son Gihoon, Park Heewoo, Kim Woon Ryoung, Park Eunjin, Choe Han Kyung, Kim Hyun, Lee Changjoong, Sun Woong, Kim Kyungjin, Shin Ki Soon, Choi Sukwoo
School of Biological Sciences, College of Natural Sciences, Seoul National University, Seoul 151-742, Korea.
Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20955-60. doi: 10.1073/pnas.0710548105.
Auditory fear memory is thought to be maintained by fear conditioning-induced potentiation of synaptic efficacy, which involves enhanced expression of surface AMPA receptor (AMPAR) at excitatory synapses in the lateral amygdala (LA). Depotentiation, reversal of conditioning-induced potentiation, has been proposed as a cellular mechanism for fear extinction; however, a direct link between depotentiation and extinction has not yet been tested. To address this issue, we applied both ex vivo and in vivo approaches to rats in which fear memory had been consolidated. A unique form of depotentiation reversed conditioning-induced potentiation at thalamic input synapses onto the LA (T-LA synapses) ex vivo. Extinction returned the enhanced T-LA synaptic efficacy observed in conditioned rats to baseline and occluded the depotentiation. Consistently, extinction reversed conditioning-induced enhancement of surface expression of AMPAR subunits in LA synaptosomal preparations. A GluR2-derived peptide that blocks regulated AMPAR endocytosis inhibited depotentiation, and microinjection of a cell-permeable form of the peptide into the LA attenuated extinction. Our results are consistent with the use of depotentiation to weaken potentiated synaptic inputs onto the LA during extinction and provide strong evidence that AMPAR removal at excitatory synapses in the LA underlies extinction.
听觉恐惧记忆被认为是通过恐惧条件反射诱导的突触效能增强来维持的，这涉及到外侧杏仁核（LA）兴奋性突触处表面AMPA受体（AMPAR）表达的增强。去增强，即条件反射诱导的增强的逆转，已被提出作为恐惧消退的一种细胞机制；然而，去增强与消退之间的直接联系尚未得到验证。为了解决这个问题，我们对恐惧记忆已巩固的大鼠采用了离体和体内方法。一种独特形式的去增强在离体状态下逆转了丘脑输入到LA的突触（T-LA突触）处的条件反射诱导的增强。消退使在条件化大鼠中观察到的增强的T-LA突触效能恢复到基线，并阻断了去增强。一致地，消退逆转了LA突触体制备中条件反射诱导的AMPAR亚基表面表达的增强。一种阻断调节性AMPAR内吞作用的GluR2衍生肽抑制了去增强，并且将该肽的细胞可渗透形式微量注射到LA中减弱了消退。我们的结果与在消退过程中使用去增强来减弱投射到LA的增强的突触输入一致，并提供了有力证据表明LA中兴奋性突触处的AMPAR移除是消退的基础。
