ALTERATION OF CALCIUM CHANNEL FUNCTION IN BRAIN AGING

钙离子通过电压门控钙通道的内流是 神经递质释放、突触可塑性、电波形 神经元基因表达的加工和修饰。然而，钙离子可以 对神经元也有有害影响；适度、持续的升高 胞浆内钙离子浓度导致神经元变性，并 最终，细胞死亡。这种对钙的侮辱已经积累起来 假设至少是大脑老化和痴呆症的某些方面的基础。 作为神经元钙信号的主要贡献者，钙通道 代表了寻找衰老来源的主要潜在目标- 相关的神经元功能障碍。事实上，它已经建立在 在过去的几年中，电压门控钙通道对 神经元中的电活动随着年龄的增长而变化。的主要目标是 项目2是为了描述衰老引起的脑组织改变的机制。 脑神经元电压门控性钙通道的活动。这项研究 该计划针对三个具体目标： (1)随着年龄的增长，钙通道的生物物理性质发生了什么变化？ (2)钙通道活性的增龄改变是否源于 钙通道的内在变化？ (3)钙通道活性的增龄改变是否源于 外在的影响？ 该实验方法利用了膜片钳的能力。 电生理学技术检测危急但潜在的 衰老过程中钙通道行为的变化。可能的属性 变化包括(I)钙电流的幅度，(Ii)电压依赖性 通道激活、失活和失活，(Iii)效率 通道开口，(Iv)通过通道的钙渗透性或(V) 对神经递质受体调节的敏感性。所有这些都是 参数将被测量并作为神经元年龄的函数进行比较。这个 生物物理和药理学工作将得到以下努力的补充 确定通道子单元组成是否随年龄变化。组织和 单细胞信使核糖核酸分析将被用作迈向这一目标的第一步。 电生理和分子生物学相结合的方法将 提供协同努力，追踪钙通道的来源 与大脑老化有关的功能障碍。了解基本机制 衰老中钙通道功能障碍的研究将在临床上发挥重要作用 治疗大脑衰老，也许还可以治疗痴呆症 阿尔茨海默氏症。

cA2+ influx through voltage-gated Ca2+ channels is essential for neurotransmitter release, synaptic plasticity, electrical waveform processing and modification of gene expression in neurons. Yet Ca2+ can also have harmful effects in neurons; modest, sustained elevation of cytoplasmic Ca2+ concentration leads to neuronal degeneration, and ultimately, cell death. Accumulation of such Ca2+ insults has been hypothesized to underlie at least some aspects of brain aging and dementia. As dominant contributors to neuronal Ca2+ signalling, Ca2+ channels represent major potential targets in the search for sources of aging- related neuronal malfunction. Indeed, it has been established over the last several years that the contribution of voltage-gated Ca2+ channels to electrical activity in neurons changes with aging. The principal goal of Project 2 is to delineate mechanisms of aging-induced alteration in the activity of voltage-gated Ca2+ channels in brain neurons. The research plan is directed towards three specific aims: (1) What biophysical properties of Ca2+ channels change with aging? (2) Does aging dependent alteration of Ca2+ channel activity arise from changes intrinsic to the Ca2+ channel? (3) Does aging-dependent alteration of Ca2+ channel activity result from extrinsic influences? The experimental approach takes of advantage of the ability of patch-clamp electrophysiological techniques to detect critical, but potentially subtile, changes in Ca2+ channel behavior in aging. Properties that may change include (i) amplitude of Ca2+ current, (ii) the voltage-dependencies of channel activation, inactivation and deactivation, (iii) efficiency of channel opening, (iv) Ca2+ permeability through the channel or (v) sensitivity to modulation by neurotransmitter-receptors. All of these parameters will be measured and compared as a function of neuron age. The biophysical and pharmacological work will be complemented by efforts to determine whether channel subunit makeup changes with aging. Tissue and single-cell mRNA analyses will be used as a first step towards this goal. The combined electrophysiological and molecular biological approach will provide a synergistic effort to track down the origins of Ca2+ channel dysfunction related to brain aging. Understanding fundamental mechanisms of Ca2+ channel dysfunction in aging will be vital in developing clinical treatments for brain senescence, and perhaps for such dementias as Alzheimer's disease.