Watabe A M, Zaki P A, O'Dell T J
Department of Physiology, University of California, Los Angeles School of Medicine, Los Angeles, California 90095, USA.
J Neurosci. 2000 Aug 15;20(16):5924-31. doi: 10.1523/JNEUROSCI.20-16-05924.2000.
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 beta-adrenergic and cholinergic receptor activation on the induction of long-term potentiation (LTP) in the hippocampal CA1 region. Low concentrations of the beta-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 beta-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 beta-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.
去甲肾上腺素能与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能和胆碱能受体相互作用是否调节被认为参与记忆形成的突触可塑性形式，我们检测了β-肾上腺素能和胆碱能受体同时激活对海马CA1区长期增强（LTP）诱导的影响。低浓度的β-肾上腺素能受体激动剂异丙肾上腺素（ISO）和胆碱能受体激动剂卡巴胆碱单独应用时，对5 Hz短暂刺激诱导LTP没有影响，但共同应用时则显著促进LTP诱导。虽然卡巴胆碱没有增强ISO诱导的cAMP增加，但ISO和卡巴胆碱共同应用可协同激活p42丝裂原活化蛋白激酶（p42 MAPK）。这表明β-肾上腺素能和胆碱能受体同时激活通过激活MAPK增强LTP诱导，而不是通过对腺苷酸环化酶的相加或协同作用。与此一致，用MEK抑制剂阻断MAPK激活可抑制β-肾上腺素能和胆碱能受体同时激活所产生的LTP诱导促进作用。虽然MEK抑制剂也抑制了在没有ISO和卡巴胆碱的情况下通过更强的5 Hz刺激方案诱导LTP，但它们对高频突触刺激或与突触后去极化配对的低频突触刺激诱导的LTP没有影响。我们的结果表明，MAPK激活在LTP诱导中具有重要的调节作用，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的趋同作用调节LTP诱导。
