# Atypical astrocytes in the aging cortex

> **NIH NIH R21** · TUFTS UNIVERSITY BOSTON · 2022 · $247,500

## Abstract

SUMMARY.
During normal aging, astrocytes change their transcriptional and functional properties. Astrocyte play a central
role in shaping neuronal function through their expression of excitatory amino acid transporters (EAATs: GLT-1
and GLAST), which mediate glutamate uptake, and the inwardly rectifying K+ channel, Kir4.1, which buffers
extracellular K+. While we know that EAAT and Kir4.1 expression are developmentally regulated, we know little
about their role in normal aging. This proposal is built on our novel finding that progressively more
astrocytes lose EAAT and Kir4.1 expression during aging. Surprisingly, this loss is not a gradual, global
change but occurs on a cell-by-cell basis with individual astrocytes expressing minimal EAAT and Kir4.1,
while neighboring astrocytes remain normal. These “atypical astrocytes” are found predominantly in the
retrosplenial and prefrontal cortices (RSC and PFC), but not in the hippocampus or somatosensory cortex.
Atypical astrocytes are more abundant in males, and grow in number as animals age. By  1 year of age, up to
15% of astrocytes are atypical in these regions. Interestingly, atypical astrocytes are not reactive, as they lack
elevated GFAP immunoreactivity. Importantly, atypical astrocytes are Sox9 positive, showing that they are in
fact astrocytes. They also do not label for NG2 (OPC marker), MBP (oligodendrocyte marker), or NeuN (neuronal
marker). Atypical astrocytes are often associated with blood vessels, but whether vascular changes contribute
to their emergence is unknown. Based on preliminary data, we hypothesize that atypical astrocytes
accumulate in the RSC and PFC during normal aging and cause domains of impaired glutamate and K+
uptake. This is significant because these areas play a prominent role in spatial memory and executive function.
If our hypothesis is correct, the loss of glutamate and K+ uptake could contribute to age-related losses in cognitive
functions associated with these regions. In addition, the combined loss of EAATs and Kir4.1 during aging may
be especially detrimental. We recently published that bursts of neuronal activity > 30 Hz drives synapse-specific
inhibition of glutamate uptake. We suspect this is due to focal K+-mediated depolarization of astrocyte distal
processes driving voltage-dependent inhibition of EAAT function. Using genetically encoded voltage indicators
(GEVIs), our preliminary data shows that astrocyte distal processes undergo significant activity-induced
depolarization, in line with voltage-dependent EAAT inhibition. Because Kir4.1 is critical to buffering extracellular
K+, its loss in aging likely exacerbates activity-induced astrocyte depolarization and increases voltage-dependent
suppression of glutamate uptake. Here, we will use electrophysiology, glutamate and GEVI imaging, and
anatomical approaches to determine whether RSC and PFC astrocytes lose expression of EAATs and Kir4.1
during aging and whether this leads to disrupted glutamate uptake ...

## Key facts

- **NIH application ID:** 10382048
- **Project number:** 1R21AG072905-01A1
- **Recipient organization:** TUFTS UNIVERSITY BOSTON
- **Principal Investigator:** Chris G Dulla
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $247,500
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10382048

## Citation

> US National Institutes of Health, RePORTER application 10382048, Atypical astrocytes in the aging cortex (1R21AG072905-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10382048. Licensed CC0.

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