# Mechanisms Underlying Glial Regulation of Neuronal Excitability in Drosophila

> **NIH NIH R21** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2020 · $193,750

## Abstract

We propose to use Drosophila as a model system for determining how glial Ca2+ oscillations
couple to K+ buffering and neurotransmitter uptake to regulate neuronal excitability. Glial cells,
including astrocytes, can increase their intracellular Ca2+ both spontaneously and in response to
neuronal activity, and growing evidence indicates astrocytic Ca2+ signaling acutely influences
neuronal physiology. However, little is known about the molecular machinery underlying
different types of glial Ca2+ signals and how they act to regulate neuronal excitability. Like
mammals, we have found that Drosophila glia display microdomain Ca2+ oscillatory activity that
acutely regulates neuronal function and behavior. Drosophila has two main glial subtypes that
are intimately associated with neurons in the CNS and that share features with mammalian
astrocytes -- astrocyte-like glia and cortex glia. The Drosophila CNS is compartmentalized into
the cell cortex that contains neuronal cell bodies, and the synaptic neuropil that contains all
neurites and synapses. Astrocytes and cortex glia are similarly compartmentalized into these
brain regions, with astrocytes associating with synapses and cortex glia surrounding neuronal
somas that are devoid of synapses. As such, Drosophila provides an ideal system to study
spatially-localized glial-neuronal signaling at somas versus synapses. We have identified
mutations in a Drosophila cortex glial-specific NCKX exchanger that controls microdomain Ca2+
oscillations and that acutely triggers neuronal seizures when inactivated. In addition, we found
that ectopic glial expression of a heat-activated TRPA1 channel can induce rapid Ca2+ influx and
neuronal seizures in cortex glial, or rapid paralysis and neuronal silencing when expressed in
astrocytes. Using unbiased genetic suppressor screens for the behavioral seizure and paralysis
phenotypes, we have generated initial data that indicates Ca2+ influx controls membrane
trafficking of either leak K+ channels or neurotransmitter transporters, providing an unexpected
and exciting connection between glial Ca2+ oscillations and the more well-known roles of glia in
K+ buffering and neurotransmitter clearance. In the current application, we propose experiments
that will provide a foundation to examine how glial Ca2+ oscillatory activity modulates spatial K+
buffering and neurotransmitter uptake to acutely modulate neuronal excitability through either
glial-soma or glial-synapse interactions, respectively.

## Key facts

- **NIH application ID:** 9936453
- **Project number:** 5R21MH120440-02
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** J. TROY LITTLETON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $193,750
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936453

## Citation

> US National Institutes of Health, RePORTER application 9936453, Mechanisms Underlying Glial Regulation of Neuronal Excitability in Drosophila (5R21MH120440-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9936453. Licensed CC0.

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