Role of L-type Ca2+ channel isoforms in the extinction of conditioned fear
Role of L-type Ca2+ channel isoforms in the extinction of conditioned fear
复制标题
DOI：
10.1101/lm.886208
复制
发表时间：
2008-05-01
影响因子：
2
通讯作者：
Singewald, Nicolas
中科院分区：
文献类型：
--
作者：
Busquet, Perrine;Hetzenauer, Alfred;Singewald, Nicolas
二氢吡啶（DHP） l型Ca2+通道（LTCC）拮抗剂，如硝苯地平，已被报道损害条件恐惧的消退而不干扰其获得。鉴定介导DHP作用的LTCC亚型是揭示其作为治疗特定焦虑症的潜在药物靶点作用的重要基础。Ca(V)1.2和Ca(V)1.3是哺乳动物大脑中主要的ltcc。然而，由于没有同种型选择性DHP阻滞剂可用，它们对恐惧记忆消退的个体贡献是未知的。为了解决这个问题，我们使用了一种表达dhp不敏感的Ca(V)1.2 ltcc (Ca（V)1.2 dhp（-/-）小鼠）的新型小鼠模型。与先前的研究一致，全身硝苯地平治疗的野生型（WT）小鼠表现出明显的恐惧消退障碍。这种DHP效应在Ca(V)1.2DHP-/-小鼠中完全消失，表明它是由Ca(V)1.2介导的，而不是由Ca(V)1.3 ltcc介导的。Ca(V)1.3缺失小鼠(Ca（V)1.3(-/-)）表现出与相应的WT小鼠相同的灭绝，支持了这一结论。脑室注射不同剂量硝苯地平后，未观察到恐惧消退的抑制作用，提示这种作用是继发于外周Ca(V)1.2通道的抑制。LTCC激活剂BayK在Ca(V)1.2DHP-/-小鼠中缺乏神经毒性作用，不影响灭绝时间过程。总之，我们证明LTCC信号通过LTCC的Ca(V)1.2亚型干扰恐惧记忆消退，可能是通过外周介导的机制。其他LTCC亚型（主要是Ca(V)1.3）的激活不足以加速小鼠条件恐惧的消失。
Dihydropyridine (DHP) L-type Ca2+ channel (LTCC) antagonists, such as nifedipine, have been reported to impair the extinction of conditioned fear without interfering with its acquisition. Identification of the LTCC isoforms mediating this DHP effect is an essential basis to reveal their role as potential drug targets for the treatment of specific anxiety disorders. Ca(V)1.2 and Ca(V)1.3 are the predominant LTCCs in the mammalian brain. However, since no isoform-selective DHP blockers are available, their individual contribution to fear memory extinction is unknown. We used a novel mouse model expressing DHP-insensitive Ca(V)1.2 LTCCs (Ca(V)1.2DHP(-/-) mice) to address this question. In line with previous studies, wild-type (WT) mice treated with systemic nifedipine displayed markedly impaired fear extinction. This DHP effect was completely abolished in Ca(V)1.2DHP-/- mice, indicating that it is mediated by Ca(V)1.2, but not by Ca(V)1.3 LTCCs. Supporting this conclusion, Ca(V)1.3-deficient mice (Ca(V)1.3(-/-)) showed extinction identical to the respective WT mice. The inhibition of fear extinction was not observed after intracerebroventricular (i.c.v.) application of different doses of nifedipine, suggesting that this effect is secondary to inhibition of peripheral Ca(V)1.2 channels. The LTCC activator BayK, which lacks neurotoxic effects in Ca(V)1.2DHP-/- mice, did not influence the extinction time course. In summary, we demonstrate that LTCC signaling through the Ca(V)1.2 isoform of LTCCs interferes with fear memory extinction, presumably via a peripherally mediated mechanism. Activation of other LTCC isoforms (predominantly Ca(V)1.3) is not sufficient to accelerate extinction of conditioned fear in mice.