Changes in cortical neurons and networks in mice overexpressing A beta

描述(申请人提供)：阿尔茨海默病(AD)是最常见的痴呆症形式。目前，65岁以上的人中约有十分之一患有AD，预计到2010年，这一数字将增长到1400万美国人。阿尔茨海默病(AD)的分子异常是众所周知的，但对导致AD临床症状的细胞和网络变化知之甚少。最近的研究表明，在AD的早期阶段，当最初的症状变得明显时，皮质网络会发生深刻的变化。我们的长期目标是确定阿尔茨海默病(AD)期间大脑皮层细胞和网络缺陷发生的时间顺序，并确定通过治疗干预可以阻止和逆转最早变化的分子靶点。在AD早期，锥体神经元是完整的，它们的细胞特性基本没有变化，但对中间神经元的细胞特性知之甚少。中间神经元在调节网络活动中起着核心作用，因此它们的性质的变化将对网络活动产生深远的影响。此外，有证据表明，在AD期间，中间神经元容易退化，中间神经元的丢失可以增强淀粉样蛋白的毒性，苯二氮卓类药物既可以逆转AD小鼠模型的一些变化，也可以减缓人类AD的进展。阿尔茨海默病期间中间神经元的改变是否会导致皮质网络的失调？我们将研究皮质中间神经元在淀粉样蛋白过度表达转基因小鼠模型中的可能作用，调查它们的细胞特性和相关的网络功能变化。具体目标1：确定中间神经元在淀粉样蛋白过度表达过程中细胞变化的时间序列，并将这些变化与锥体神经元中的变化进行比较。我们将通过使用电生理记录和钙成像技术，研究不同年龄的淀粉样蛋白过度表达的小鼠和野生型小鼠脑片中中间神经元和锥体神经元的细胞特性来回答这个问题。具体目标2：描述在淀粉样蛋白过度表达过程中皮质网络的变化，并研究这些变化是否可能是抑制和兴奋的失衡所致。我们将使用电生理记录和钙成像技术研究麻醉小鼠的网络功能。这些研究将为阿尔茨海默病中间神经元可能的退化以及由此导致的皮质网络调节失调提供关键的洞察力。我们希望这些信息对成功开发AD的新疗法是必不可少的。阿尔茨海默病是最常见的痴呆症，目前65岁以上的人中约有十分之一患有阿尔茨海默病。人们对导致阿尔茨海默病临床症状的单个神经元和神经网络的变化知之甚少。我们将在阿尔茨海默病小鼠模型中研究抑制性中间神经元的变化，这是神经网络的关键调节因素。这些研究将为阿尔茨海默病中发生的细胞变化以及由此导致的神经网络退化提供关键的洞察力。

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common form of dementia. AD currently affects approximately one in ten people over 65 years of age and this number is expected to grow to 14 million Americans by 2010. The molecular aberrations that underlie Alzheimer's disease (AD) are well-described, but relatively little is known about the resulting cellular and network changes which lead to the clinical symptoms of AD. Recent studies show that cortical networks are profoundly altered during the early stages of AD, when initial symptoms become apparent. Our long-term objective is to determine the temporal order in which cellular and network defects occur in the cerebral cortex during Alzheimer's disease (AD) and to identify molecular targets through which the earliest changes can be arrested and reversed by therapeutic intervention. During early AD, pyramidal neurons are intact and their cellular properties are largely unchanged, but little is known about the cellular properties of interneurons. Interneurons play a central role in regulating network activity so changes in their properties would have a profound effect on network activity. Furthermore, there is evidence that interneurons are susceptible to degeneration during AD, that loss of interneurons can enhance ¿-amyloid toxicity and that benzodiazepines can both reverse some changes in mouse models of AD and slow progression of AD in humans. Do changes in interneurons lead to dysregulation of cortical networks during AD? We will investigate the possible roles of cortical interneurons in a transgenic mouse model of ¿-amyloid overexpression, investigating both their cellular properties and the associated changes in network function. Specific aim 1: To determine the temporal sequence of cellular changes in interneurons during ¿-amyloid overexpression and compare these changes with those in pyramidal neurons. We will answer this by examining the cellular properties of interneurons and pyramidal neurons in brain slices from ¿-amyloid overexpressing mice and wild-type littermates at different ages, using electrophysiological recording and calcium imaging techniques. Specific aim 2: To describe the changes in cortical networks during ¿-amyloid overexpression and investigate whether these changes are likely to result from an imbalance of inhibition and excitation. We will study network function in anesthetized mice using electrophysiological recording and calcium imaging techniques. These studies will provide critical insight into the possible degeneration of interneurons in AD and the resulting dysregulation of cortical networks. We expect this information to be essential for the successful development of novel therapies for AD. Alzheimer's disease is the most common form of dementia and currently affects approximately one in ten people over 65 years of age. Little is known about the changes in individual neurons and neural networks which lead to the clinical symptoms of Alzheimer's disease. We will study changes in inhibitory interneurons, which are key regulators of neural networks, in a mouse model of Alzheimer's disease. These studies will provide critical insight into the cellular changes that occur in Alzheimer's disease and the resulting degeneration of neural networks.