The cardinal symptom of individuals with Alzheimer’s disease (AD) is progressive loss of long-term memory. Multiple pathologic mechanisms, including amyloid-b (Ab) plaques and neurofibrillary tangles (NFTs), contribute to AD. Early memory dysfunction in AD is thought to arise from synaptic dysfunction that progresses within entorhinal-hippocampal circuits along the trisynaptic pathway. But how AD disrupts information storage encoded by neuronal networks maintaining long-term memory within these circuits could not be investigated, because the persistent molecular mechanisms maintaining stability of the networks were unknown. However, the parent grant R01MH115304 investigates a persistently active atypical PKC (aPKC) isoform, PKMz, that is a core molecular mechanism for maintaining LTP, long-term memory, and stable entorhinal- hippocampal network activity dynamics. We discovered that after its initial synthesis, persistent interactions between PKMz and the human memory- and AD-linked, postsynaptic scaffolding protein, KIBRA, maintain late- LTP and long-term memory. Compensatory mechanisms substitute for this core mechanism in PKMz-null mice, when the other aPKC, PKCi/l, becomes persistently active to sustain LTP and store suboptimal memory. By calcium-imaging, we find that CA1 ensemble activity dynamics express a long-term representation of spatial memories internally organized as a 2-D manifold. This organization is disturbed by PKMz inhibition, improves with experience, and crucially constrains memory-related ensemble activity patterns. Thus, our overall hypothesis is Ab (and in future studies NFTs and neuroinflammation) disrupts core and suboptimal compensatory aPKC maintenance mechanisms within neuronal ensembles that organize and encode long-term memories. Supplementary Aim 1 tests whether aPKC dysregulation, in a hierarchy of PKMz- KIBRA loss and PKCi/l compensation, is a feature of the deficits of LTP maintenance during development of Ab-producing, amyloid precursor protein/presenilin 1 (APP/PS1) mutant mice. In preliminary data, we observe decreased PKMz together with increased PKCi/l in CA1 pyramidal cells of aged APP/PS1 mice, suggesting suboptimal compensation. Supplementary Aim 2 tests whether PKMz downregulates in APP/PS1 mice at dendritic sites of spatial memory storage, and where entorhinal inputs terminate that express PKMz without memory-dependent increases, which we hypothesize organize manifold dynamics that are the substrate for memory formation. In Supplementary Aim 3, we will record CA1 neural activity for weeks by imaging GCaMP6f in behaving APP/PS1 mice and controls, to measure both memory-task information and the 2-D manifold dynamics in the patterns of activity. These 3 Supplementary Aims are: 1) within the scope of R01MH115304, 2) will elucidate how AD pathology causally disrupts the fundamental mechanisms of memory maintenance in neuronal networks, and 3) will stimulate progress by pioneering a strategy for studying th...