School of Physiology, Pharmacology and Neuroscience, University of Bristol , Bristol , United Kingdom.
University of Exeter Medical School , Exeter , United Kingdom.
J Neurophysiol. 2019 Mar 1;121(3):773-784. doi: 10.1152/jn.00334.2018. Epub 2019 Jan 9.
Action potential firing in hippocampal pyramidal neurons is regulated by generation of an afterhyperpolarization (AHP). Three phases of AHP are recognized, with the fast AHP regulating action potential firing at the onset of a burst and the medium and slow AHPs supressing action potential firing over hundreds of milliseconds and seconds, respectively. Activation of β-adrenergic receptors suppresses the slow AHP by a protein kinase A-dependent pathway. However, little is known regarding modulation of the medium AHP. Application of the selective β-adrenergic receptor agonist isoproterenol suppressed both the medium and slow AHPs evoked in rat CA1 hippocampal pyramidal neurons recorded from slices maintained in organotypic culture. Suppression of the slow AHP was mimicked by intracellular application of cAMP, with the suppression of the medium AHP by isoproterenol still being evident in cAMP-dialyzed cells. Suppression of both the medium and slow AHPs was antagonized by the β-adrenergic receptor antagonist propranolol. The effect of isoproterenol to suppress the medium AHP was mimicked by two β-adrenergic receptor agonists, BRL37344 and SR58611A. The medium AHP was mediated by activation of small-conductance calcium-activated K channels and deactivation of H channels at the resting membrane potential. Suppression of the medium AHP by isoproterenol was reduced by pretreating cells with the H-channel blocker ZD7288. These data suggest that activation of β-adrenergic receptors inhibits H channels, which suppresses the medium AHP in CA1 hippocampal neurons by utilizing a pathway that is independent of a rise in intracellular cAMP. This finding highlights a potential new target in modulating H-channel activity and thereby neuronal excitability. NEW & NOTEWORTHY The noradrenergic input into the hippocampus is involved in modulating long-term synaptic plasticity and is implicated in learning and memory. We demonstrate that activation of functional β-adrenergic receptors suppresses the medium afterhyperpolarization in hippocampal pyramidal neurons. This finding provides an additional mechanism to increase action potential firing frequency, where neuronal excitability is likely to be crucial in cognition and memory.
动作电位在海马锥体神经元中的发放受到后超极化（AHP）的产生调节。AHP 可分为三个阶段，其中快速 AHP 在爆发起始时调节动作电位的发放，而中速和慢速 AHP 分别在数百毫秒和数秒内抑制动作电位的发放。β-肾上腺素能受体的激活通过蛋白激酶 A 依赖性途径抑制慢速 AHP。然而，对于中速 AHP 的调节知之甚少。应用选择性β-肾上腺素能受体激动剂异丙肾上腺素可抑制在器官型培养中保持的切片中记录的大鼠 CA1 海马锥体神经元的中速和慢速 AHP。细胞内应用 cAMP 模拟了对慢速 AHP 的抑制，并且异丙肾上腺素对中速 AHP 的抑制在 cAMP 透析细胞中仍然明显。β-肾上腺素能受体拮抗剂普萘洛尔拮抗两种 AHP 的抑制。异丙肾上腺素抑制中速 AHP 的作用被两种β-肾上腺素能受体激动剂 BRL37344 和 SR58611A 模拟。中速 AHP 是通过激活小电导钙激活的 K 通道和在静息膜电位下失活 H 通道介导的。用 H 通道阻断剂 ZD7288 预处理细胞可降低异丙肾上腺素对中速 AHP 的抑制作用。这些数据表明，β-肾上腺素能受体的激活抑制 H 通道，通过利用一种不依赖于细胞内 cAMP 增加的途径，抑制 CA1 海马神经元中的中速 AHP。这一发现突出了调节 H 通道活性从而调节神经元兴奋性的潜在新靶点。新的和值得注意的是，去甲肾上腺素能输入到海马体参与调节长期突触可塑性，并与学习和记忆有关。我们证明，功能性β-肾上腺素能受体的激活抑制海马锥体神经元中的中速后超极化。这一发现提供了另一种增加动作电位发放频率的机制，而神经元兴奋性很可能在认知和记忆中至关重要。
