# Astrocyte regulation of synapse maturation

> **NIH NIH R01** · SALK INSTITUTE FOR BIOLOGICAL STUDIES · 2020 · $420,875

## Abstract

In the developing brain excitatory synapses first form containing calcium permeable AMPA glutamate receptors
(AMPARs), which are replaced by GluA2 containing calcium impermeable AMPARs as synapses stabilize and
mature. The switch from calcium-permeable to calcium-impermeable AMPARs contributes to synapse
maturation and limits subsequent synaptic plasticity, by limiting the entry of calcium into the postsynaptic cell.
Studies have shown that the presence of astrocytes is sufficient to increase surface and synaptic levels of all 4
AMPAR subunits (GluA1-4) in neurons, and have identified glypicans 4 & 6 as astrocyte-secreted signals that
specifically recruit GluA1 calcium-permeable AMPARs to synapses, with no effect on GluA2. This raised the
hypothesis that astrocytes can regulate the subunit composition of AMPARs at synapses by releasing distinct
signals, which has the potential to alter synapse maturation and plasticity. A screen was conducted to identify
the GluA2 recruiting factor and identified the astrocyte-secreted BMP antagonist chordin like 1 (Chrdl1).
Addition of Chrdl1 to neurons in vitro is sufficient to increase synaptic clustering of GluA2, and to induce
functionally mature synapses to form. In vivo, Chrdl1 is specifically expressed by astrocytes in the mouse brain
and absent from neurons. Expression of Chrdl1 is restricted to cortical astrocytes, and within the cortex
expression is higher in astrocytes in upper cortical layers compared to deep, and peaks at the time of synapse
maturation and synaptic recruitment of GluA2. Mice globally lacking Chrdl1 show evidence of delayed synapse
maturation, with altered kinetics of synaptic transmission and decreased levels of GluA2 at excitatory
synapses. This proposal investigates unanswered questions related to: 1) how Chrdl1 is interacting with
neurons to recruit GluA2 to synapses, 2) what regulates the regional and temporal expression of Chrdl1 in
astrocytes, 3) whether lack of Chrdl1 in vivo enhances synaptic plasticity. Aim 1 investigates whether Chrdl1 is
acting in its known role as a secreted antagonist of BMP signaling, either through the canonical BMP pathway
or in a non-canonical mechanism. Aim 2 asks if the in vivo expression pattern of Chrdl1 is due to specific
patterns of neuronal innervation, and asks what is the signal from neurons that induces Chrdl1 in astrocytes. In
Aim 3, the question of whether the impaired synapse maturation and immature synapses observed in Chrdl1
KO mice leads to enhanced synaptic plasticity is investigated in the visual system, by looking at the role of
Chrdl1 in critical period plasticity. These experiments will give important mechanistic insight into how synapse
maturation is controlled in the developing brain, and the role of astrocytes in this process.

## Key facts

- **NIH application ID:** 9828113
- **Project number:** 5R01NS105742-03
- **Recipient organization:** SALK INSTITUTE FOR BIOLOGICAL STUDIES
- **Principal Investigator:** Nicola J Allen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $420,875
- **Award type:** 5
- **Project period:** 2018-03-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828113

## Citation

> US National Institutes of Health, RePORTER application 9828113, Astrocyte regulation of synapse maturation (5R01NS105742-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828113. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*