Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory
Critical role of the 65-kDa isoform of glutamic acid decarboxylase in consolidation and generalization of Pavlovian fear memory
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DOI：
10.1101/lm.705408
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发表时间：
2008-03-01
影响因子：
2
通讯作者：
Stork, Oliver
中科院分区：
文献类型：
--
作者：
Bergado-Acosta, Jorge R.;Sangha, Susan;Stork, Oliver
有证据表明，杏仁核和海马GABA能系统的可塑性对恐惧记忆的形成至关重要。在这项研究中，我们调查了野生型和基因操作小鼠的活动依赖性65 kDa的谷氨酸脱羧酶（GAD 65）的同工酶的作用，在巩固和推广的条件性恐惧。首先，我们证明了短暂的减少GAD 65基因表达的背海马（6小时后的训练）和杏仁核（24小时后的训练）在不同阶段的恐惧记忆巩固的基底外侧复合体。第二，我们表明，Gad 65（-/-）小鼠的GAD 65基因的靶向消融导致在长期（24小时或14天），但不是短期（30分钟）的记忆检索的听觉恐惧记忆的显着的上下文无关的，模态内泛化。Gad 65突变小鼠的基因调控和记忆缺陷的时间特异性表明，GAD 65介导的GABA合成是巩固刺激特异性恐惧记忆的关键。该功能似乎涉及调节杏仁核-海马通路中的神经活动模式，如Gad 65（-/-）小鼠在表达广义恐惧记忆期间杏仁核和海马之间的θ频率同步减少所示。
Evidence suggests that plasticity of the amygdalar and hippocampal GABAergic system is critical for fear memory formation. In this study we investigated in wild-type and genetically manipulated mice the role of the activity-dependent 65-kDa isozyme of glutamic acid decarboxylase (GAD65) in the consolidation and generalization of conditioned fear. First, we demonstrate a transient reduction of GAD65 gene expression in the dorsal hippocampus (6 h post training) and in the basolateral complex of the amygdala (24 h post training) during distinct phases of fear memory consolidation. Second, we show that targeted ablation of the GAD65 gene in Gad65(-/-) mice results in a pronounced context-independent, intramodal generalization of auditory fear memory during long-term (24 h or 14 d) but not short-term (30 min) memory retrieval. The temporal specificity of both gene regulation and memory deficits in Gad65 mutant mice suggests that GAD65-mediated GABA synthesis is critical for the consolidation of stimulus-specific fear memory. This function appears to involve a modulation of neural activity patterns in the amygdalo-hippocampal pathway as indicated by a reduction in theta frequency synchronization between the amygdala and hippocampus of Gad65(-/-) mice during the expression of generalized fear memory.