PKMzeta inhibition reverses learning-induced increases in hippocampal synaptic strength and memory during trace eyeblink conditioning.
PKMzeta inhibition reverses learning-induced increases in hippocampal synaptic strength and memory during trace eyeblink conditioning.
复制标题
DOI：
10.1371/journal.pone.0010400
复制
发表时间：
2010-04-29
期刊：
影响因子：
3.7
通讯作者：
Delgado-García JM
中科院分区：
文献类型：
--
作者：
Madroñal N;Gruart A;Sacktor TC;Delgado-García JM
记忆形成过程中的一个主要候选者是海马长时程增强(LTP)，这是一种由兴奋性突触的重复激活而引起的突触强度的持续增强，无论是通过实验性的高频刺激(HFS)，还是最近显示的，在实际学习过程中。但是，维持HFS诱导突触增强的分子机制和经验诱导的分子机制相同吗？蛋白激酶Mzeta(PKMζ)是一种自主激活的非典型蛋白激酶C亚型，在强直性刺激诱导的长时程增强的维持和长时记忆的存储中起着关键作用。为了验证PKMζ的持续作用是否对学习后突触增强的维持是必需的，我们研究了PKMζ抑制剂ZIP对瞬目条件反射小鼠的影响。在海马区抑制PKMζ既破坏了条件性反应(CRs)的正确恢复，也破坏了观察到的CA3-CA1突触的经验依赖性突触强度的持续增加。此外，在条件化前用强直性LTP诱导大鼠海马CA3-CA1突触时，还观察了ZIP对同一联想实验的影响。在这种情况下，PKMζ抑制既逆转了强直性长时程增强，又阻止了长时程增强对眨眼条件反射的预期有害影响。因此，在CA1区抑制PKMζ既能逆转痕量眨眼条件记忆的表达，又能逆转CA3CA1突触强度的潜在变化，以及LTP对联想学习的顺行效应。
A leading candidate in the process of memory formation is hippocampal long-term potentiation (LTP), a persistent enhancement in synaptic strength evoked by the repetitive activation of excitatory synapses, either by experimental high-frequency stimulation (HFS) or, as recently shown, during actual learning. But are the molecular mechanisms for maintaining synaptic potentiation induced by HFS and by experience the same? Protein kinase Mzeta (PKMζ), an autonomously active atypical protein kinase C isoform, plays a key role in the maintenance of LTP induced by tetanic stimulation and the storage of long-term memory. To test whether the persistent action of PKMζ is necessary for the maintenance of synaptic potentiation induced after learning, the effects of ZIP (zeta inhibitory peptide), a PKMζ inhibitor, on eyeblink-conditioned mice were studied. PKMζ inhibition in the hippocampus disrupted both the correct retrieval of conditioned responses (CRs) and the experience-dependent persistent increase in synaptic strength observed at CA3-CA1 synapses. In addition, the effects of ZIP on the same associative test were examined when tetanic LTP was induced at the hippocampal CA3-CA1 synapse before conditioning. In this case, PKMζ inhibition both reversed tetanic LTP and prevented the expected LTP-mediated deleterious effects on eyeblink conditioning. Thus, PKMζ inhibition in the CA1 area is able to reverse both the expression of trace eyeblink conditioned memories and the underlying changes in CA3-CA1 synaptic strength, as well as the anterograde effects of LTP on associative learning.
登录
查看更多内容
影响因子：
9.8
作者：
Serrano, Peter;Friedman, Eugenia L.;Kenney, Jana;Taubenfeld, Stephen M.;Zimmerman, Joshua M.;Hanna, John;Alberini, Cristina;Kelley, Ann E.;Maren, Stephen;Rudy, Jerry W.;Yin, Jerry C. P.;Sacktor, Todd C.;Fenton, Andre A.
通讯作者：
Fenton, Andre A.
影响因子：
56.9
作者：
Moser, EI;Krobert, KA;Morris, RGM
通讯作者：
Morris, RGM
影响因子：
5.5
作者：
BLISS, TVP;GARDNERM.AR
通讯作者：
GARDNERM.AR
影响因子：
6.1
作者：
Gureviciene, I;Ikonen, S;Tanila, H
通讯作者：
Tanila, H
影响因子：
2.5
作者：
Thompson, LT;Moyer, JR;Disterhoft, JF
通讯作者：
Disterhoft, JF