Coactivation of β-Adrenergic and Cholinergic Receptors Enhances the Induction of Long-Term Potentiation and Synergistically Activates Mitogen-Activated Protein Kinase in the Hippocampal CA1 Region
Coactivation of β-Adrenergic and Cholinergic Receptors Enhances the Induction of Long-Term Potentiation and Synergistically Activates Mitogen-Activated Protein Kinase in the Hippocampal CA1 Region
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DOI：
10.1523/jneurosci.20-16-05924.2000
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发表时间：
2000-08
期刊：
影响因子：
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通讯作者：
A. M. Watabe;P. Zaki;T. O’Dell
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文献类型：
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作者：
A. M. Watabe;P. Zaki;T. O’Dell
去甲肾上腺素能和胆碱能受体信号之间的相互作用在某些形式的学习中可能很重要。为了研究去甲肾上腺素和胆碱能受体的相互作用是否调节被认为与记忆形成有关的突触可塑性的形式，我们检测了同时激活β-肾上腺素和胆碱能受体对诱导海马CA1区长时程增强的影响。低浓度的β肾上腺素能受体激动剂异丙肾上腺素和胆碱能受体激动剂卡巴胆碱单独应用时对短时5赫兹刺激诱导的长时程增强无影响，但在联合应用时显著促进长时程增强。虽然卡巴胆碱不能增强ISO诱导的cAMP升高，但ISO和卡巴胆碱联合应用可协同激活p42丝裂原活化蛋白激酶(P42 MAPK)。这表明同时激活β-肾上腺素能和胆碱能受体是通过激活MAPK而不是通过对腺苷酸环化酶的相加或协同作用来增强LTP的诱导。与此一致的是，用MEK抑制剂阻断MAPK的激活，抑制了由β-肾上腺素能和胆碱能受体同时激活所产生的LTP诱导的便利化。尽管MEK抑制剂也抑制了5赫兹刺激方案的LTP的诱导，这种刺激方案在没有ISO和卡巴胆碱的情况下诱导LTP，但它们对高频突触刺激或低频突触刺激结合突触后去极化诱导的LTP没有影响。我们的结果表明，MAPK的激活在LTP的诱导中具有重要的调制作用，并提示去甲肾上腺素能和胆碱能受体的共同激活通过对MAPK的汇聚作用来调节LTP的诱导。
Interactions between noradrenergic and cholinergic receptor signaling may be important in some forms of learning. To investigate whether noradrenergic and cholinergic receptor interactions regulate forms of synaptic plasticity thought to be involved in memory formation, we examined the effects of concurrent β-adrenergic and cholinergic receptor activation on the induction of long-term potentiation (LTP) in the hippocampal CA1 region. Low concentrations of the β-adrenergic receptor agonist isoproterenol (ISO) and the cholinergic receptor agonist carbachol had no effect on the induction of LTP by a brief train of 5 Hz stimulation when applied individually but dramatically facilitated LTP induction when coapplied. Although carbachol did not enhance ISO-induced increases in cAMP, coapplication of ISO and carbachol synergistically activated p42 mitogen-activated protein kinase (p42 MAPK). This suggests that concurrent β-adrenergic and cholinergic receptor activation enhances LTP induction by activating MAPK and not by additive or synergistic effects on adenylyl cyclase. Consistent with this, blocking MAPK activation with MEK inhibitors suppressed the facilitation of LTP induction produced by concurrent β-adrenergic and cholinergic receptor activation. Although MEK inhibitors also suppressed the induction of LTP by a stronger 5 Hz stimulation protocol that induced LTP in the absence of ISO and carbachol, they had no effect on LTP induced by high-frequency synaptic stimulation or low-frequency synaptic stimulation paired with postsynaptic depolarization. Our results indicate that MAPK activation has an important, modulatory role in the induction of LTP and suggest that coactivation of noradrenergic and cholinergic receptors regulates LTP induction via convergent effects on MAPK.