# Trans-synaptic mechanism of retinal synapse formation and function

> **NIH NIH R00** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $322,211

## Abstract

PROJECT SUMMARY
Retinal neurons establish synaptic connections with specialized functional properties to achieve
parallel visual information processing. We recently identified a trans-synaptic mechanism that
coordinates the precise alignment between pre-synaptic neurotransmitter release site and post-
synaptic receptors complex at retinal photoreceptor synapses. The key organizer for this trans-
synaptic complex is α2δ4, a protein traditionally known as the auxiliary subunit of voltage gated
calcium channels (VGCCs). We showed that α2δ4 controls photoreceptor synapse formation
through regulating VGCC mediated Ca2+ influx and interacting with synaptogenic cell adhesion
molecules. Our findings have important relevance to Alzheimer’s Disease (AD), of which the
hallmarks are amyloid β (Aβ) deposit and synaptic degeneration. Growing evidence supports
that Aβ induces synaptotoxicity through disrupting Ca2+ influx through VGCC which leads to all
major molecular and cellular alterations in AD. However, the molecular basis underlying Aβ
induced VGCC functional change and the downstream signaling linking VGCC dysfunction to
synaptic deficits remain largely unknown.
Retinas in AD individuals also have Aβ deposits and display impaired synaptic morphology and
function which are associated with cognitive performance, suggesting that synapses in the
retina and brain respond to Aβ in a similar fashion and that retinal synapses may provide
informative biomarkers for the pathology of AD. However, the molecular mechanism underlying
Aβ induced retinal synaptic changes remains virtually unknown. We hypothesize that
extracellular α2δ proteins are key mediators for Aβ triggered VGCC dysfunction and that
downstream effectors of disrupted VGCC function serve as convergent signaling mechanism
underlying synaptic dysfunction in AD. The long-term goal of this proposed study is to uncover
the molecular basis of synaptic degeneration in AD and develop mechanism-based clinical
interventions. The objective of the proposed work is to study the role of previously identified key
synaptic organizer, α2δ4, in AD related retinal synaptic deficit and to identify key signaling
pathways underlying synaptic degeneration in AD retina. This proposal is significant in that it
has the potential to uncover previously unappreciated and understudied basic biochemical
pathways related to AD which will stimulate exciting future AD mechanistic studies.

## Key facts

- **NIH application ID:** 10940047
- **Project number:** 3R00EY030554-06S1
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Yuchen Wang
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $322,211
- **Award type:** 3
- **Project period:** 2019-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10940047

## Citation

> US National Institutes of Health, RePORTER application 10940047, Trans-synaptic mechanism of retinal synapse formation and function (3R00EY030554-06S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10940047. Licensed CC0.

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