Departments of Otolaryngology and Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA.
J Neurosci. 2011 Mar 2;31(9):3158-68. doi: 10.1523/JNEUROSCI.5303-10.2011.
Cholinergic neuromodulation controls long-term synaptic plasticity underlying memory, learning, and adaptive sensory processing. However, the mechanistic interaction of cholinergic, neuromodulatory inputs with signaling pathways underlying long-term potentiation (LTP) and long-term depression (LTD) remains poorly understood. Here, we show that physiological activation of muscarinic acetylcholine receptors (mAChRs) controls the size and sign of associative long-term synaptic plasticity via interaction with endocannabinoid signaling. Our findings indicate that synaptic or pharmacological activation of postsynaptic M1/M3 converts postsynaptic Hebbian LTP to presynaptic anti-Hebbian LTD in principal neurons of the dorsal cochlear nucleus (DCN). This conversion is also dependent on NMDA receptor (NMDAR) activation and rises in postsynaptic Ca(2+). While NMDAR activation and Ca(2+) elevation lead to LTP, when these events are coordinated with simultaneous activation of M1/M3 mAChRs, anti-Hebbian LTD is induced. Anti-Hebbian LTD is mediated by a postsynaptic G-protein-coupled receptor intracellular signaling cascade that activates phospholipase C and that leads to enhanced endocannabinoid signaling. Moreover, the interaction between postsynaptic M1/M3 mAChRs and endocannabinoid signaling is input specific, as it occurs only in the parallel fiber inputs, but not in the auditory nerve inputs innervating the same DCN principal neurons. Based on the extensive distribution of cholinergic and endocannabinoid signaling, we suggest that their interaction may provide a general mechanism for dynamic, context-dependent modulation of associative synaptic plasticity.
胆碱能神经调制控制着记忆、学习和适应性感觉处理的长期突触可塑性。然而，胆碱能、神经调制输入与长时程增强（LTP）和长时程抑制（LTD）的信号通路的机械相互作用仍知之甚少。在这里，我们表明，毒蕈碱型乙酰胆碱受体（mAChRs）的生理激活通过与内源性大麻素信号的相互作用控制着联想性长期突触可塑性的大小和符号。我们的发现表明，背侧耳蜗核（DCN）中的主神经元中，突触或药理学激活突触后 M1/M3 将突触后赫布型 LTP 转换为突触前反赫布型 LTD。这种转换还依赖于 NMDA 受体（NMDAR）的激活和突触后 Ca(2+)的增加。虽然 NMDAR 的激活和 Ca(2+)的升高导致 LTP，但当这些事件与同时激活 M1/M3 mAChRs 协调时，会诱导出反赫布型 LTD。反赫布型 LTD 是由突触后 G 蛋白偶联受体细胞内信号级联介导的，该级联激活磷脂酶 C，从而增强内源性大麻素信号。此外，突触后 M1/M3 mAChRs 和内源性大麻素信号之间的相互作用是输入特异性的，因为它仅发生在平行纤维输入中，而不在支配相同 DCN 主神经元的听神经输入中发生。基于胆碱能和内源性大麻素信号的广泛分布，我们认为它们的相互作用可能为联想性突触可塑性的动态、上下文相关调节提供了一种普遍机制。
