# Trans-synaptic mechanism of retinal synapse formation and function

> **NIH NIH R00** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $249,000

## Abstract

Our optimal visual performance starts with the correct parallel visual information processing in the retina
which depends on precise retinal neural circuit formation. To achieve this, retinal neurons must accurately set
up functional synapses which require precise alignment between the pre-synaptic neurotransmitter releasing site
and the post-synaptic receptor. Increasing evidence suggests that cell adhesion molecules (CAMs)-mediated
trans-synaptic complexes are critical for synapse formation and function, however, the mechanism how pre-
synaptic releasing machinery coordinates with the post-synaptic receptor signaling complex at retinal ribbon
synapses is largely unknown. We recently reported that the extracellular calcium channel auxiliary subunit α2δ4
is necessary for rod photoreceptor axonal elaboration and synapse formation and demonstrated that α2δ4 does
so through controlling the synaptic targeting of ELFN1, a leucine-rich repeat (LRR) protein specifically expressed
at rod synapse and interacts trans-synaptically with the post-synaptic mGluR6 receptor. We also showed that
α2δ4 interacts with ELFN1 through the LRR domain, a conserved domain shared across many LRR proteins.
Interestingly, we and other lab identified another LRR protein termed LRIT1, which specifically affects cone
synaptic function. The objective of the proposed work is to determine whether it is a general mechanism that
pre-synaptic calcium channel complex utilizes α2δ4 to coordinate with post-synaptic receptor through the
facilitation of different LRR proteins. In Aim 1, we will determine the functional role of α2δ4-ELFN1 interaction in
rod synapse formation using in vivo electroporation combined with deletion mutagenesis. In Aim 2, we will study
how LRIT1 regulates cone synaptic function by testing whether LRIT1 affects pre-synaptic Cav1.4 channel
activity through α2δ4 using electrophysiological recording. In Aim 3, I will investigate whether synapses in the
inner plexiform layer (IPL) also adopt similar trans-synaptic mechanism by studying how α2δ4 and LRIT1 affect
RBC-AII amacrine synapse formation and function using the technique gained during the mentored phase. This
proposal is innovative because no mechanistic studies has been done on α2δ4 protein despite its clearly
important role in photoreceptor synapse formation and function. The proposed work is significant since results
from this study will enable better understanding of how retinal neurons establish and maintain synaptic contact.

## Key facts

- **NIH application ID:** 10914964
- **Project number:** 5R00EY030554-06
- **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:** $249,000
- **Award type:** 5
- **Project period:** 2019-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914964

## Citation

> US National Institutes of Health, RePORTER application 10914964, Trans-synaptic mechanism of retinal synapse formation and function (5R00EY030554-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10914964. Licensed CC0.

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