Differential impact of Alzheimer disease on neuronal subpopulations in dorsal hippocampal CA1

项目总结/文摘

PROJECT SUMMARY/ABSTRACT Memory loss in early Alzheimer disease (AD) appears when pathophysiology extends from entorhinal cortex (EC) into hippocampal area CA1. CA1 processes EC input to generate hippocampal output, and bears the brunt of hippocampal AD pathology. AD studies on CA1 have treated its pyramidal neurons (PNs) as a homogeneous population. However, work from our and other groups established that CA1 PNs are diverse, comprised of superficial (sPN) and deep (dPN) layers with unique roles in memory. The two layers show differential changes in ischemia and epilepsy, but our knowledge of AD pathophysiology at this level is incomplete. This limits our understanding of memory deficits in AD and our ability to correct dysfunction. This knowledge can also advance our understanding of activity-dependent spread of AD and neurodegeneration risk factors. Our published and preliminary data, and the literature, support a working hypothesis that dorsal CA1 sPNs and dPNs exhibit contrasting pathophysiological and functional compromise due to amyloid and tau pathology. The sPNs develop pathologic signs of aging, and show intrinsic and synaptic hypoexcitability in aged and 3xTg-AD mice. The dPNs do not show these signs and become hyperexcitable. In human AD, the sPN layer is more prone to plaques and tangles, and the two layers show proteomic differences related to disease pathways and excitability. We test our hypothesis using amyloid (5xFAD) and tau (PS19) models to separately address the effects of these pathologies on sPNs/dPNs at three levels. In Aim 1, we use in vitro opto-electrophysiology to evaluate the impact of AD pathology on dorsal sPN- versus dPN-associated circuits. This will relate cell and synaptic identity to the directionality and extent of physiologic change. We expect that amyloid/tau induce hypoexcitability in sPN circuits and hyperexcitability in dPN circuits. In Aim 2, we use miniscope GCaMP calcium imaging to determine the influence of AD pathology on dorsal sPN versus dPN activity during hippocampal-dependent behavior. This will test the in vivo dominance of differential local circuit changes in CA1 over globally reduced efferent input in the setting of memory deficits. We expect that sPNs are more vulnerable to reductions in their in vivo activity during memory-guided behaviors. In Aim 3, we compare proteomic changes in dorsal sPNs versus dPNs in the setting of AD pathology. This will link cell identity, molecular markers of AD severity, and the degree/directionality of physiologic change. We expect that sPN proteomes will show more severe changes in pathologic AD pathways. This work is significant by providing new, cell-type specific, mechanistic knowledge about memory dysfunction in AD. This will also help link physiologic change to development of pathology and neurodegeneration. These are critical steps towards better treatments. Our strategy is innovative by combining multiple, state-of-the-art approaches to address disease pathophysiology in distinct cell types at multiple biological levels: circuit, behavior, and molecular.