Agmon Ariel, Wells Jason E
Department of Neurobiology and Anatomy and the Sensory Neuroscience Research Center, West Virginia University, Morgantown, West Virginia 26506-9128, USA.
J Neurosci. 2003 May 1;23(9):3658-68. doi: 10.1523/JNEUROSCI.23-09-03658.2003.
Under both pathological and experimental conditions, area CA3 of the adult or juvenile hippocampus generates periodic population discharges known as interictal bursts. Whereas the ionic and synaptic basis of individual bursts has been comprehensively studied experimentally and computationally, the pacemaker mechanisms underlying interictal rhythmicity remain conjectural. We showed previously that rhythmic population discharges resembling interictal bursts can be induced in hippocampal slices from first postnatal week mice, in Mg2+-free solution with GABA(A) receptor-mediated inhibition blocked. Here we show that these neonatal bursts occurred with high temporal precision and that their frequency and regularity were greatly reduced by the bradycardic agent ZD-7288 when applied at concentrations and durations that selectively block the hyperpolarization-activated, cationic current I(h). Augmenting I(h) by elevating intracellular cAMP dramatically increased burst frequency in a protein kinase A-independent manner. Burst amplitudes were strongly correlated with the preceding, but not the following, interburst intervals. The experimentally observed distribution of interburst intervals was modeled by assuming that a burst was triggered whenever the instantaneous rate of spontaneous EPSPs (sEPSPs) exceeded a threshold and that the mean sEPSP rate was minimal immediately after a burst and then relaxed exponentially to a steady-state level. The effect of blocking I(h) in any given slice could be modeled by decreasing only the steady-state sEPSP rate, suggesting that the instantaneous rate of sEPSPs is governed by the level of I(h) activation and raising the novel possibility that interburst intervals reflected the slow activation kinetics of I(h) in the neonatal CA3.
在病理和实验条件下，成年或幼年海马体的CA3区会产生周期性群体放电，即发作间期爆发。尽管单个爆发的离子和突触基础已通过实验和计算进行了全面研究，但发作间期节律的起搏器机制仍存在推测。我们之前表明，在出生后第一周小鼠的海马切片中，在无镁溶液中且GABA(A)受体介导的抑制被阻断时，可以诱导出类似发作间期爆发的节律性群体放电。在这里我们表明，这些新生爆发具有很高的时间精度，并且当以选择性阻断超极化激活的阳离子电流I(h)的浓度和持续时间应用缓慢性心律失常药物ZD-7288时，它们的频率和规律性会大大降低。通过提高细胞内cAMP来增强I(h)，以一种不依赖蛋白激酶A的方式显著增加了爆发频率。爆发幅度与之前的而非之后的爆发间隔时间密切相关。通过假设每当自发兴奋性突触后电位（sEPSPs）的瞬时速率超过阈值时就会触发一次爆发，并且在一次爆发后sEPSP的平均速率立即最小化，然后呈指数级松弛到稳态水平，对实验观察到的爆发间隔时间分布进行了建模。在任何给定切片中阻断I(h)的效果可以通过仅降低稳态sEPSP速率来建模，这表明sEPSPs的瞬时速率受I(h)激活水平的控制，并提出了一种新的可能性，即爆发间隔时间反映了新生CA3中I(h)的缓慢激活动力学。
