Deficiency of the 65 kDa Isoform of Glutamic Acid Decarboxylase Impairs Extinction of Cued But Not Contextual Fear Memory
Deficiency of the 65 kDa Isoform of Glutamic Acid Decarboxylase Impairs Extinction of Cued But Not Contextual Fear Memory
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DOI：
10.1523/jneurosci.2620-09.2009
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发表时间：
2009-12-16
影响因子：
5.3
通讯作者：
Pape, Hans-Christian
中科院分区：
文献类型：
--
作者：
Sangha, Susan;Narayanan, Rajeevan T.;Pape, Hans-Christian
消退程序在临床上与减少病理性恐惧相关，并且恐惧调节机制是深入研究的主题。杏仁核、海马体和前额皮质（PFC）都被认为是消除条件性恐惧的关键大脑区域。 GABA 尤其与灭绝学习有关，并且 65 kDa 的谷氨酸脱羧酶 (GAD65) 亚型可能在响应环境信号而提高 GABA 水平方面发挥重要作用。在 Gad65(-/-) 小鼠中检查条件性恐惧的消退情况，同时记录杏仁核、海马和 PFC 的局部场电位，同时监测行为。正如之前报道的，Gad65(-/-) 小鼠表现出提示恐惧的泛化，并且提示恐惧的消退受损，使得在消退训练中恐惧仍然很高。这种对暗示恐惧的耐受力与杏仁核和海马体之间的θ频率同步有关。然而，与野生型同窝小鼠相比，Gad65(-/-) 小鼠的情境恐惧消除没有改变。数据表明，GAD65 在调节消退学习过程中的提示恐惧反应中发挥着关键作用，并且在此过程中，GABA 信号参与调节杏仁核和海马体之间的同步活动。鉴于对暗示恐惧消退的影响比情境恐惧消退的影响更明显，这些影响可能更多地依赖于杏仁核中的 GABA 能机制。
Extinction procedures are clinically relevant for reducing pathological fear, and the mechanisms of fear regulation are a subject of intense research. The amygdala, hippocampus, and prefrontal cortex (PFC) have all been suggested to be key brain areas in extinction of conditioned fear. GABA has particularly been implicated in extinction learning, and the 65 kDa isoform of glutamic acid decarboxylase (GAD65) may be important in elevating GABA levels in response to environmental signals. Extinction of conditioned fear was examined in Gad65(-/-) mice while recording local field potentials from the amygdala, hippocampus, and PFC simultaneously while monitoring behavior. Gad65(-/-) mice showed generalization of cued fear, as reported previously, and impaired extinction of cued fear, such that fear remained high across extinction training. This endurance in cued fear was associated with theta frequency synchronization between the amygdala and hippocampus. Extinction of contextual fear, however, was unaltered in Gad65(-/-) mice when compared with wild-type litter-mates. The data imply that GAD65 plays a critical role in regulating cued fear responses during extinction learning and that, during this process, GABAergic signaling is involved in modulating synchronized activity between the amygdala and hippocampus. In view of the more pronounced effect on cued versus contextual fear extinction, these influences may rely more on GABAergic mechanisms in the amygdala.