# Molecular mechanisms of memory maintenance and dysfunction in neural circuits

> **NIH NIH R01** · SUNY DOWNSTATE MEDICAL CENTER · 2022 · $417,138

## Abstract

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...

## Key facts

- **NIH application ID:** 10498522
- **Project number:** 3R01MH115304-05S1
- **Recipient organization:** SUNY DOWNSTATE MEDICAL CENTER
- **Principal Investigator:** ANDRE ANTONIO FENTON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $417,138
- **Award type:** 3
- **Project period:** 2018-06-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10498522

## Citation

> US National Institutes of Health, RePORTER application 10498522, Molecular mechanisms of memory maintenance and dysfunction in neural circuits (3R01MH115304-05S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10498522. Licensed CC0.

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