Cox C L, Metherate R, Ashe J H
Department of Neuroscience, University of California, Riverside 92521.
Synapse. 1994 Feb;16(2):123-36. doi: 10.1002/syn.890160206.
Muscarinic-type acetylcholine (ACh) receptor are involved in a variety of cortical functions. ACh "activates" neocortex; simultaneously modifying spontaneous subthreshold activity, intrinsic neuronal oscillations and spike discharge modes, and responsiveness to fast (putative glutamatergic) synaptic inputs. However, beyond the general involvement of muscarinic receptors, a mechanistic understanding of integrated cholinergic actions, and interactions with non-cholinergic transmission, is lacking. We have addressed this problem using intracellular recordings from the in vitro auditory neocortex. First, we investigated cholinergic modification of responses to the excitatory amino acid glutamate. ACh, or the muscarinic agonist methacholine, produced a lasting enhancement of glutamate-mediated membrane depolarizations. Muscarinic receptors of the M1 and/or M3 subtype, rather than M2 or nicotinic receptors, mediated this enhancement. Subsequently, we investigated whether second messenger systems contribute to observed muscarinic actions. Activation of protein kinase C with phorbol 12,13-dibutyrate (4 beta-PDBu), enhanced neuronal responses to glutamate. The effect of 4 beta-PDBu was attenuated by the kinase antagonist H7. Finally, we attempted to identify postsynaptic actions of endogenous ACh. Tetanic stimulation of cholinergic afferents elicited voltage-dependent effects, including reduced spike frequency adaptation and reduced slow afterhyperpolarization (sAHP) elicited by transmembrane depolarizing stimuli. These effects were mimicked by methacholine, enhanced by eserine, and antagonized by muscarinic receptor antagonists. These data suggest that cholinergic modulation in neocortex likely involves the integrated actions of diverse mechanisms, primarily gated by muscarinic receptors, and at least partly involving second messenger systems.
毒蕈碱型乙酰胆碱（ACh）受体参与多种皮质功能。乙酰胆碱“激活”新皮质；同时改变自发阈下活动、内在神经元振荡和动作电位发放模式，以及对快速（推测为谷氨酸能）突触输入的反应性。然而，除了毒蕈碱受体的普遍参与外，目前缺乏对胆碱能综合作用及其与非胆碱能传递相互作用的机制性理解。我们使用体外听觉新皮质的细胞内记录来解决这个问题。首先，我们研究了胆碱能对兴奋性氨基酸谷氨酸反应的调节作用。乙酰胆碱或毒蕈碱激动剂醋甲胆碱可使谷氨酸介导的膜去极化产生持久增强。M1和/或M3亚型的毒蕈碱受体而非M2或烟碱受体介导了这种增强作用。随后，我们研究了第二信使系统是否参与观察到的毒蕈碱作用。用佛波酯12,13 - 二丁酸酯（4β - PDBu）激活蛋白激酶C可增强神经元对谷氨酸的反应。4β - PDBu的作用被激酶拮抗剂H7减弱。最后，我们试图确定内源性乙酰胆碱的突触后作用。对胆碱能传入纤维的强直刺激引发电压依赖性效应，包括降低动作电位频率适应性以及由跨膜去极化刺激引发的慢后超极化（sAHP）减弱。这些效应可被醋甲胆碱模拟，被毒扁豆碱增强，并被毒蕈碱受体拮抗剂拮抗。这些数据表明，新皮质中的胆碱能调制可能涉及多种机制的综合作用，主要由毒蕈碱受体门控，并且至少部分涉及第二信使系统。
