Changes in cortical neurons and networks in mice overexpressing A beta

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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.