# Glutamate neurotransmission in Alzheimer's disease progression

> **NIH NIH R01** · SOUTHERN ILLINOIS UNIVERSITY SCH OF MED · 2020 · $583,085

## Abstract

Project Summary/Abstract
In spite of the evidence supporting the involvement of the glutamatergic system in Alzheimer’s
disease (AD), research has focused on indirect measures of glutamate (Glu) involvement, mainly
through increased downstream pathways related to excitotoxicity, without addressing possible
changes in extracellular Glu occurring during disease progression. Knowledge of basal and
phasic extracellular Glu levels and clearance kinetics would allow us to establish an early
biomarker, better determine and explore novel therapeutic targets, and establish the opportune
treatment window that has the potential to alter AD progression. Until recently, research
measuring extracellular Glu levels has been limited because few techniques are capable of in
vivo analysis within small sub-regions of the brain. We have developed a MEA that, when
combined with electrochemistry, has the ability to measure micromolar changes in basal and
phasic extracellular Glu with high temporal (msec) and spatial (micron) resolution during acute
and chronic recordings. We plan to use this technique to address our central hypothesis that
alterations in extracellular Glu in awake animals occur prior to cognitive decline and
neuropathology associated with AD, and that Aβ accumulation with age potentiates these
changes resulting in the cognitive decline typical in AD. This hypothesis will be evaluated using
a novel knock-in mouse model of AD, APPNL-F/NL-F mice, and APP/PS1 mice, and their respective
controls at 2-4, 8-10, and 18-20 months of age. At these ages, one cohort of mice will undergo
cognitive evaluation using the Morris water maze followed by awake stimulus (KCl)-evoked Glu
recordings in the CA1 region of the hippocampus. These studies will help us determine if basal
Glu and Glu release (presynaptic) and uptake (glia and postsynaptic) kinetics are altered in AD
mice and if so, how and when these alterations occur over the continuum of cognitive and
pathophysiological decline. Next, to determine if alterations in Glu neurotransmission is
behaviorally detrimental, we will examine a second group of mice at the same ages and
hippocampal sub-region during a memory related task, the spontaneous alternation y maze. This
will allow us to determine the impact of aging and AD progression on formation and recall of
memories in the form of phasic Glu measurements. Taken together, we anticipate that these
studies will give us valuable insight into the role of Glu as an early biomarker, a mechanism for
disease progression, a site for potential novel therapeutic targets, and optimal intervention
timeframes for AD.

## Key facts

- **NIH application ID:** 9906833
- **Project number:** 5R01AG057767-03
- **Recipient organization:** SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
- **Principal Investigator:** Erin R Hascup
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $583,085
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906833

## Citation

> US National Institutes of Health, RePORTER application 9906833, Glutamate neurotransmission in Alzheimer's disease progression (5R01AG057767-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9906833. Licensed CC0.

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