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.