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Trans-synaptic mechanism of retinal synapse formation and function

Award Number: R00EY030554
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Trans-synaptic mechanism of retinal synapse formation and function - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	6	8/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $571,211 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	001	6	8/15/2024	SUPPLEMENT FOR EXPANSION	$322,211
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	6	8/12/2024	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $571,211

Issue Date FY: 2023 ( Subtotal = $248,928 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	001	5	8/28/2023	NON-COMPETING CONTINUATION	$248,927
2023	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	4	7/2/2023	EXTENSION WITH OR WITHOUT FUNDS	$1
														Subtotal = $248,928

Issue Date FY: 2022 ( Subtotal = $248,999 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	4	8/31/2022	EXTENSION WITH OR WITHOUT FUNDS	$248,999
														Subtotal = $248,999

Grand Total All Awards = $1,069,138

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Trans-synaptic mechanism of retinal synapse formation and function

Award Number: R00EY030554

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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