# Synapse structural dynamics and memory loss in mouse models of Alzheimers disease

> **NIH NIH R01** · UNIVERSITY OF KANSAS LAWRENCE · 2020 · $250,000

## Abstract

PROJECT SUMMARY/ABSTRACT
The efficacy of memory storage is determined by the delicate balance between excitatory and inhibitory
synaptic strength and connectivity (E/I balance). The goal of this proposal is to understand how the disruption
of this balance in cortical neurons leads to memory loss in mouse models of Alzheimer's disease (AD).
 Immunohistology of postmortem brains from the AD patients shows that the reduction in excitatory
synapse density is the strongest correlate for the severity of memory loss. A reduction in excitatory synapse
density would lower neuronal activity. In contrast, brain imaging studies identified neuronal hyperactivity in
clinically healthy individuals with a genetic predisposition for AD. Mouse models of AD, with human familial AD-
linked mutations in the gene coding for amyloid precursor protein (APP mice), also display reduced excitatory
synapses and neuronal hyperactivity. In this proposal, we will experimentally reconcile these contrasting
observations and determine the synaptic deficits associated with memory loss in APP mice.
 Neuronal activity is maintained around a set point within a dynamic range. Any perturbation to this
range elicits compensatory synaptic changes to achieve homeostasis. Therefore, we hypothesize that the
reduction in excitatory synapse density in APP mice is a homeostatic adaptation to hyperactivity triggered by
E/I imbalance. The reduction in excitatory synapses then causes long-term memory loss.
We recently developed a novel approach to label and repeatedly image excitatory and inhibitory
synaptic proteins in the same cortical neurons in vivo using multicolor two-photon microscopy. This approach
has allowed us to simultaneously visualize excitatory and inhibitory synapse dynamics in the mouse brain in
vivo with an unprecedented resolution. In addition, we have established a paradigm for assessing accelerated
forgetting (normal short-term but an impaired long-term memory) in APP mice. Accelerated forgetting was
recently discovered in clinically healthy individuals with APP mutations. Our preliminary studies indicate that
the APP mice form a visual recognition memory (VRM) but are unable to stabilize it as long-term memory.
 Using chronic in vivo synapse imaging and the VRM task in APP mice (J20 and 5X-FAD lines), we will
determine 1) whether excitatory synapse loss is a homeostatic adaptation to hyperactivity and whether the
initial E/I imbalance is triggered by impairments to excitatory or inhibitory synapses; 2) whether hyperactivity
prevents the stabilization of excitatory synapses formed during learning and leads to accelerated forgetting;
and 3) the relative contribution of impaired stabilization of new synapses and accelerated destabilization of
synaptic proteins in pre-existing synapses in reducing excitatory synapse density.
 The proposed studies will provide the highest resolution examination of synapses in APP mice in vivo
to date and reveal synaptic impairments that precede m...

## Key facts

- **NIH application ID:** 10137656
- **Project number:** 3R01AG064067-02S1
- **Recipient organization:** UNIVERSITY OF KANSAS LAWRENCE
- **Principal Investigator:** Jaichandar Subramanian
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $250,000
- **Award type:** 3
- **Project period:** 2019-07-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137656

## Citation

> US National Institutes of Health, RePORTER application 10137656, Synapse structural dynamics and memory loss in mouse models of Alzheimers disease (3R01AG064067-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10137656. Licensed CC0.

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