# Astrocyte regulation of neuronal AMPA glutamate receptors

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2023 · $420,875

## Abstract

ABSTRACT
This project addresses the role of astrocytes in regulating neuronal synapses, specifically by regulating levels
of AMPA glutamate receptors (AMPARs) at postsynaptic sites. Astrocyte-secreted glypican 4 and 6 (Gpc4&6)
are sufficient to induce nascent synapses by clustering calcium-permeable GluA1 AMPA receptors on the
postsynaptic dendrite. Further, the mechanism Gpc4 employs is by signaling through presynaptic protein
tyrosine phosphatase receptor delta, to induce release of the AMPAR clustering factor neuronal pentraxin 1. In
this proposal the mouse visual cortex (VC) will be used to study the relative contribution of astrocyte-expressed
glypicans to synapse formation, maturation and plasticity. Preliminary studies showed Gpc4&6 are most highly
expressed by astrocytes at the time of synapse formation, fitting with their role inducing nascent synapses,
while another astrocyte enriched glypican, Gpc5, is upregulated with synapse maturation and remains high in
the adult, suggesting it may regulate synapse maturation or plasticity. This proposal addresses 3 questions
related to the role of astrocyte-enriched glypicans in the formation and maturation of excitatory synapses in the
VC. 1) What is the role of astrocyte-expressed Gpc5 in synapse maturation and plasticity? Mice lacking Gpc5
in astrocytes have decreased presynaptic size of thalamo-cortical synapses, and altered recruitment of
postsynaptic AMPARs. Based on this it is hypothesized that Gpc5 regulates presynaptic maturation, which will
be investigated using electrophysiology, immunohistochemistry and electron microscopy. Further, as Gpc4&6
regulate GluA1 AMPARs in development, the hypothesis that Gpc5 is required to increase synaptic levels of
GluA1 during plasticity in the adult brain will be tested. 2) What is the role of Gpc4 in excitatory synapse
formation onto inhibitory interneurons? Whether astrocytes regulate excitatory synapses onto inhibitory
interneurons (INs) is an important unanswered question. As synapses onto INs contain high levels of GluA1
AMPARs, which Gpc4 regulates on principal neurons, it is hypothesized that Gpc4 induces synapses onto INs.
Preliminary experiments found a deficit in GluA1 on IN dendrites in the Gpc4 KO. This study will investigate the
mechanism underlying this deficit using electrophysiology and immunohistochemistry; ask if the same
synaptogenic pathway is employed as at principal neuron synapses; and if lack of Gpc4 affects plasticity at IN
synapses. 3) What is the relative contribution of astrocyte-expressed Gpc4&6 to synaptic function? Gpc4&6
are redundant in vitro in inducing synaptic activity. Preliminary studies found Gpc4&6 have different spatial and
temporal expression in the developing VC, leading to the hypothesis they have stage and synapse-specific
roles in synaptogenesis. This will be analyzed using astrocyte-specific Gpc4 and Gpc6 single KO mice, and
astrocyte-specific Gpc4/Gpc6 double KO mice, and synapse formation and function ac...

## Key facts

- **NIH application ID:** 10624965
- **Project number:** 5R01NS089791-10
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Nicola J Allen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $420,875
- **Award type:** 5
- **Project period:** 2014-09-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10624965

## Citation

> US National Institutes of Health, RePORTER application 10624965, Astrocyte regulation of neuronal AMPA glutamate receptors (5R01NS089791-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10624965. Licensed CC0.

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