Convergent Metabotropic Signaling Pathways Inhibit SK Channels to Promote Synaptic Plasticity in the Hippocampus.
Convergent Metabotropic Signaling Pathways Inhibit SK Channels to Promote Synaptic Plasticity in the Hippocampus.
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DOI：
10.1523/jneurosci.1160-18.2018
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发表时间：
2018-10-24
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影响因子：
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通讯作者：
Mellor JR
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文献类型：
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作者：
Tigaret CM;Chamberlain SEL;Sadowski JHLP;Hall J;Ashby MC;Mellor JR
海马 Schaffer 侧支突触的 Hebbian 突触可塑性受到限制 NMDA 受体活性的突触后小电导 (SK) 通道的严格调节。 SK 通道本身受到 G 蛋白偶联信号通路的调节，但尚不清楚这些通路在什么条件下被激活以实现突触可塑性。在这里，我们发现，毒蕈碱 M1 受体 (M1R) 和 1 型代谢型谷氨酸受体 (mGluR1) 信号通路已知可抑制 SK 通道，从而抑制 NMDA 受体，在雄性大鼠海马 Schaffer 侧支突触诱导长期增强 (LTP) 至 CA1 锥体神经元期间，它们会聚合以促进脊柱钙瞬变。此外，mGluR1 激活是由重新激活的位置细胞放电模式诱导的 LTP 所必需的，这种放电模式在休息或睡眠期间的尖波纹波事件中发生。相比之下，在探索过程中，位置细胞放电模式诱导的 LTP 需要 M1R 激活。因此，我们描述了一种常见机制，可以在海马回路内的记忆编码和巩固过程中实现突触可塑性。意义陈述 海马体中的记忆群是在主动探索过程中形成的，并在休息或睡眠过程中巩固的。这两个不同的阶段都需要通过长时程增强 (LTP) 来加强突触连接。每个阶段的神经元活动模式都非常不同，这使得很难将 LTP 诱导的通用规则映射到形成和巩固阶段。在这项研究中，我们发现突触后 SK 通道的抑制是 LTP 诱导的一个常见的必要特征，并且 SK 通道的抑制是通过独立但会聚的代谢信号通路来实现的。因此，我们揭示了在不同行为条件下启用 LTP 的通用机制。
Hebbian synaptic plasticity at hippocampal Schaffer collateral synapses is tightly regulated by postsynaptic small conductance (SK) channels that restrict NMDA receptor activity. SK channels are themselves modulated by G-protein-coupled signaling pathways, but it is not clear under what conditions these are activated to enable synaptic plasticity. Here, we show that muscarinic M1 receptor (M1R) and type 1 metabotropic glutamate receptor (mGluR1) signaling pathways, which are known to inhibit SK channels and thereby disinhibit NMDA receptors, converge to facilitate spine calcium transients during the induction of long-term potentiation (LTP) at hippocampal Schaffer collateral synapses onto CA1 pyramidal neurons of male rats. Furthermore, mGluR1 activation is required for LTP induced by reactivated place-cell firing patterns that occur in sharp-wave ripple events during rest or sleep. In contrast, M1R activation is required for LTP induced by place-cell firing patterns during exploration. Thus, we describe a common mechanism that enables synaptic plasticity during both encoding and consolidation of memories within hippocampal circuits. SIGNIFICANCE STATEMENT Memory ensembles in the hippocampus are formed during active exploration and consolidated during rest or sleep. These two distinct phases each require strengthening of synaptic connections by long-term potentiation (LTP). The neuronal activity patterns in each phase are very different, which makes it hard to map generalized rules for LTP induction onto both formation and consolidation phases. In this study, we show that inhibition of postsynaptic SK channels is a common necessary feature of LTP induction and that SK channel inhibition is achieved by separate but convergent metabotropic signaling pathways. Thus, we reveal a common mechanism for enabling LTP under distinct behavioral conditions.