Functional Aspects of Calcium‐Channel Modulation
Functional Aspects of Calcium‐Channel Modulation
复制标题
钙通道调节的功能方面
作者：
J. Disterhoft;J. Moyer;Lucien T. Thompson;M. Kowalska
总结：联想学习伴随着大脑中的许多变化，其中许多是由钙介导的。我们利用眨眼条件反射来解释这些变化，这是一种动物和人类都能很好地控制的学习任务。我们的研究集中在海马体上，海马体是一种颞叶结构，在哺乳动物大脑学习过程中对新信息的存储很重要。海马神经元在学习过程中表现出与行为习得相关的增强放电率；它们还显示出钙介导的后超极化（AHP）的减少，这可能是它们活性增强的机制。衰老的动物和人类表现出学习缺陷；衰老海马神经元表现出ahp增加和钙缓冲改变，这是导致行为学习缺陷的原因。静脉注射钙拮抗剂尼莫地平使年老的兔子学习眨眼调节任务的速度与年轻的对照组一样快。口服尼莫地平提高老龄兔子、大鼠和猴子的学习率。在每种情况下，所分析的学习任务类型都依赖于海马体对习得的处理，并随着年龄的增长而受损。尼莫地平还能逆转大鼠和家兔在野外行为中与衰老相关的改变。我们对尼莫地平在增强衰老家兔海马神经元活动中的可能作用进行了一系列的生理研究。这些研究的目的是确定尼莫地平如何在细胞水平上起作用以提高学习率。从我们的数据中可以得出四个主要结论：(a)尼莫地平在体内以衰老和浓度依赖的方式强烈增强了单个海马锥体神经元的放电率。其他钙通道阻滞剂，如硝苯地平和氟桂嗪，用于控制脑血流变化，基本上对海马放电率没有影响。(b)衰老家兔海马切片中，由外向钙活化钾电流介导的慢速AHP在锥体神经元中明显增大。尼莫地平浓度低至100 nM时，可可靠地降低衰老锥体细胞的ahp。衰老的神经元也比年轻的神经元表现出更多的脉冲频率适应或调节。尼莫地平在低至10 nMin的浓度下部分阻断了老化神经元的调节。(c)老龄神经元钙动作电位增大。尼莫地平对钙动作电位的调节呈年龄和浓度依赖性；低至100 nM的浓度降低了老化CA1神经元中的钙动作电位，而对年轻细胞没有影响。(d)尼莫地平阻断急性游离海马锥体神经元的高阈值非失活钙电流（L型钙电流）。这种效应很快消失，并在应用双氢吡啶钙通道激动剂Bay K 8644后逆转。这些在体内和体外收集的数据表明，尼莫地平直接作用于已知在眨眼条件反射中起重要作用的神经元元件。这种直接的神经元行为应该有助于改善老化的大脑的学习能力。我们的工作的临床意义在于尝试使用尼莫地平治疗阿尔茨海默病或老年学习障碍。老化的人类大脑中的许多学习缺陷可能是由过量的神经元钙介导的，并且应该可以通过钙通道拮抗剂进行干预。
Summary: Associative learning is accompanied by a number of changes in the brain, many mediated by calcium. We have used eyeblink conditioning, a wellcontrolled learning task in animals and humans, to elucidate these changes. Our studies have focused on the hippocampus, a temporal lobe structure known to be important for storage of new information during learning in mammalian brain. Hippocampal neurons show an enhanced firing rate during learning correlated with behavioral acquisition; they also show reduction in a calcium‐mediated afterhyperpolarization (AHP), a likely mechanism for their enhanced activity. Aging animals and humans exhibit learning deficits; aging hippocampal neurons show increased AHPs and altered calcium buffering, which contribute to the behavioral learning deficits. Intravenous administration of the calcium antagonist nimodipine causes aging rabbits to learn the eyeblink conditioning task as quickly as young controls. Oral nimodipine enhances learning rates in aging rabbits, rats, and monkeys. In each case, the type of learning task analyzed is dependent on hippocampal processing for acquisition and is impaired with aging. Nimodipine also reverses aging‐related alterations in open field behavior of both rats and rabbits. We have done a series of physiological studies focused on the possible role of nimodipine in enhancing neuronal activity in the hippocampus of aging rabbits. The purpose of these studies was to determine how nimodipine may be functioning at a cellular level to increase the learning rate. Four major conclusions may be drawn from our data: (a) Nimodipine strongly enhanced the firing rate of single hippocampal pyramidal neurons recorded in vivo in an aging‐ and concentration‐dependent fashion. Other calcium‐channel blockers, such as nifedipine and flunarizine, given to control for cerebral blood flow changes, had essentially no effect on the hippocampal firing rate. (b) The slow AHP, mediated by an outward calcium‐activated potassium current, was markedly larger in pyramidal neurons in hippocampal slices prepared from aging rabbits. Nimodipine, at concentrations as low as 100 nM, reliably reduced the AHPs of aging pyramidal cells. Aging neurons also showed more spike frequency adaptation, or accomodation, than young neurons. Nimodipine partially blocked accomodation at concentrations as low as 10 nMin aging neurons. (c) The calcium action potential was larger in aging neurons. Nimodipine modulated the calcium action potential in an ageand concentration‐dependent fashion; concentrations as low as 100 nM reduced the calcium action potential in aging CA1 neurons without effects on young cells. (d) Nimodipine blocked the high threshold, noninactivating calcium current (L‐ type calcium current) in acutely dissociated hippocampal pyramidal neurons. This effect quickly washed out and was reversed with application of Bay K 8644, a dihydropyridine calcium‐channel agonist. These data, gathered both in vivo and in vitro, suggest that nimodipine acts directly on neuronal elements known to be importantly involved in eyeblink conditioning. Such direct neuronal action should help to improve learning in aging brain. The clinical implications of our work lie in the attempt to use nimodipine to treat Alzheimer disease or learning deficits in the aging. Many of the learning deficits in aging human brain may be importantly mediated by excess neuronal calcium and should be amenable to intervention with a calcium‐channel antagonist.