McKinney Brandon C, Sze Wilson, White Jessica A, Murphy Geoffrey G
Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan 48109, USA.
Learn Mem. 2008 Apr 25;15(5):326-34. doi: 10.1101/lm.893808. Print 2008 May.
Using pharmacological approaches, others have suggested that L-type voltage-gated calcium channels (L-VGCCs) mediate both consolidation and extinction of conditioned fear. In the absence of L-VGCC isoform-specific antagonists, we have begun to investigate the subtype-specific role of LVGCCs in consolidation and extinction of conditioned fear using a molecular genetics approach. Previously, we used this approach to demonstrate that the Ca(v)1.3 isoform mediates consolidation, but not extinction, of contextually conditioned fear. Here, we used mice in which the gene for the L-VGCC pore-forming subunit Ca(v)1.2 was conditionally deleted in forebrain excitatory neurons (Ca(v)1.2(cKO) mice) to address the role of Ca(v)1.2 in consolidation and extinction of conditioned fear. We demonstrate that Ca(v)1.2(cKO) mice consolidate and extinguish conditioned fear as well as control littermates. These data suggest that Ca(v)1.2 is not critical for these processes and together with our previous data argue against a role for either of the brain-expressed L-VGCCs (Ca(v)1.2 or Ca(v)1.3) in extinction of conditioned fear. Additionally, we present data demonstrating that the L-VGCC antagonist nifedipine, which has been used in previous conditioned fear extinction studies, impairs locomotion, and induces an aversive state. We further demonstrate that this aversive state can enter into associations with conditioned stimuli that are present at the time that it is experienced, suggesting that previous studies using nifedipine were likely confounded by drug toxicity. Taken together, our genetic and pharmacological data argue against a role for Ca(v)1.2 in consolidation of conditioned fear as well as a role for L-VGCCs in extinction of conditioned fear.
其他人通过药理学方法提出，L型电压门控钙通道（L-VGCCs）介导条件性恐惧的巩固和消退。在缺乏L-VGCC亚型特异性拮抗剂的情况下，我们已开始使用分子遗传学方法研究LVGCCs在条件性恐惧巩固和消退中的亚型特异性作用。此前，我们使用该方法证明Ca(v)1.3亚型介导情境性条件性恐惧的巩固，但不介导消退。在此，我们使用在前脑兴奋性神经元中条件性缺失L-VGCC孔形成亚基Ca(v)1.2基因的小鼠（Ca(v)1.2(cKO)小鼠）来研究Ca(v)1.2在条件性恐惧巩固和消退中的作用。我们证明Ca(v)1.2(cKO)小鼠在巩固和消退条件性恐惧方面与对照同窝小鼠一样。这些数据表明Ca(v)1.2对这些过程并不关键，并且与我们之前的数据一起表明，大脑中表达的两种L-VGCCs（Ca(v)1.2或Ca(v)1.3）在条件性恐惧消退中均不起作用。此外，我们提供的数据表明，先前在条件性恐惧消退研究中使用的L-VGCC拮抗剂硝苯地平会损害运动，并诱导厌恶状态。我们进一步证明，这种厌恶状态可与经历该状态时出现的条件刺激建立关联，这表明先前使用硝苯地平的研究可能受到药物毒性的混淆。综上所述，我们的遗传学和药理学数据表明Ca(v)1.2在条件性恐惧巩固中不起作用，以及L-VGCCs在条件性恐惧消退中不起作用。
