# The influence of axonal ER on retrograde synapse loss following axon damage

> **NIH NIH R21** · XONA MICROFLUIDICS, LLC · 2020 · $413,392

## Abstract

Axon injury is an early event of neurotrauma that leads to retrograde cellular changes, including somatic ER
stress, synapse loss, hyper-excitability, and even cell death. Foundational work remains needed to understand
how axon-to-soma injury signals propagate to effect these profound retrograde changes in long projection
pyramidal cells. Understanding this signaling is critical for the future development of neuroprotective
approaches. Axon injury causes massive influx of calcium into the cytosol to initiate axon-to-soma signaling,
leading to transcription-dependent retrograde synapse loss and hyperexcitability. Evidence suggests either an
endoplasmic reticulum (ER)-dependent calcium wave or calcium-primed microtubule-based transport mediates
this long-range axon-to-soma signaling. A vast ER network extends throughout the neuron from distal axon
terminals to dendritic spines, influencing the availability of calcium, but the extent of axonal ER involvement in
axon injury-induced synapse loss and hyper-excitability remains unknown. Further, while rat injury models are
a mainstay of this research, it remains unclear how human glutamatergic neurons, with their diminished
regenerative capacity, differ in their injury signaling mechanisms. Experimentally tractable multi-compartment,
microfluidic chambers enable manipulation of axons independently from somata and dendrites, providing an
important tool to investigate axon-to-soma communication in both murine and human stem cell-derived neurons.
We found that hippocampal pyramidal neurons subjected to distal axotomy in our microfluidic chambers undergo
somatic ER stress, retrograde synapse loss, and hyper-excitability. Reducing calcium influx locally at the site of
injury and blocking transcription prevents axotomy-induced dendritic spine loss; thus, calcium signaling and
rapid transcription mediate synapse loss following axon injury. Our long-term goal is to identify key molecular
players and their timing of action that cause retrograde synapse loss and hyper-excitability following axon injury.
Aim 1 will determine the influence of axonal ER on axotomy-induced somatic ER stress in both rat and human
glutamatergic neurons. Aim 2 will examine the influence of axonal ER signaling on axotomy-induced synapse
loss and hyper-excitability. Together, this study provides a critical first step in defining the role of ER during
axon-to-soma injury signaling in pyramidal cells. Further, this project may lead to the novel identification of
therapeutics during early stages of neuron damage and will likely have broader implications for other
neurological disorders where both ER stress and axon damage are prevalent.

## Key facts

- **NIH application ID:** 9894123
- **Project number:** 1R21NS109750-01A1
- **Recipient organization:** XONA MICROFLUIDICS, LLC
- **Principal Investigator:** ANNE MARION TAYLOR
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $413,392
- **Award type:** 1
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894123

## Citation

> US National Institutes of Health, RePORTER application 9894123, The influence of axonal ER on retrograde synapse loss following axon damage (1R21NS109750-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9894123. Licensed CC0.

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