Wednesday, July 2, 2025 7/2/2025

Excitability and Excitotoxicity in Type-I Cochlear Afferents: Synapse Structure and Function

Award Number: R01DC014712
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/10/2016
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Excitability and Excitotoxicity in Type-I Cochlear Afferents: Synapse Structure and Function - Project Summary: This project investigates the cochlear AMPA-type glutamate receptors (AMPARs) that are necessary for hearing, overactivation of which leads to excitotoxic synapse loss and hearing disorders. Each cochlear afferent synapse expresses many hundreds to a few thousand of these AMPARs, of both the Ca2+-permeable subtype (CP-AMPARs, lacking subunit GluA2) and the Ca2+-impermeable subtype (CI-AMPARs, containing subunit GluA2). The combination of pore-forming GluA subunits and auxiliary subunits of the AMPAR complex, influenced by transsynaptic adhesion factors, determine its physiological properties and pharmacological sensitivities. The cochlear AMPAR complex has properties that make it unique in the nervous system, for example, the absence of GluA1. However, the precise complement of cochlear AMPAR subunits in not known. This proposal uses mouse genetics, in vivo and ex vivo cochlear electrophysiology, proteomics, and ultrastructural molecular anatomy to investigate the subunit composition, pharmacological sensitivity, and functional significance of the cochlear AMPAR complex. We will determine the influence of auxiliary subunit TARP-2 (Stargazin) on cochlear function, synaptic transmission, and GluA subunit expression. We will test the hypothesis that synaptopathy in GluA3KO mice results from an increase in Ca2+-permeability of the AMPAR complex. We will determine how Neuroligin1 and 3 affect AMPAR subunit expression and auditory nerve fiber physiology. We will determine the influence of GluA3, TARP-2, Nlgn1, and Nlgn3 on the intrasynaptic distribution of AMPAR subunits. With recombinant expression of different combinations of GluA pore-forming and auxiliary subunits in HEK cells (with or without GluA3, with or without TARP-2), we will challenge our understanding of the cochlear AMPAR complex by comparing changes in pharmacological sensitivity with those changes observed for the native cochlear synapses (GluA3WT vs GluA3KO, TARP-2WT vs TARP-2KO). The gain of this basic knowledge will inform design of small molecules to target cochlear AMPARs. With chronic systemic administration of the tool compound (CP-AMPAR blocker IEM-1925), we will measure synaptic adaptation and resistance to noise-induced synaptopathy. With acute systemic dosing, we will ask if noise trauma can be prevented if IEM-1925 is given only during, not before, the noise exposure and if IEM- 1925 + antioxidant combination therapy can protect cochlear function from more intense noise exposures. The long-term goal of this line of investigation is to develop systemic drugs to target CP-AMPARs of the inner ear while allowing hearing function to be maintained through CI-AMPARs, and while avoiding unwanted CNS side effects. The successful completion of this collaborative project will determine the precise subunit composition of the cochlear AMPAR complex and its influence on pharmacological sensitivity.


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 = $553,928 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	000	9	3/5/2025	NON-COMPETING CONTINUATION	$553,928
														Subtotal = $553,928

Issue Date FY: 2024 ( Subtotal = $621,655 )
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Research Related to Deafness and Communication Disorders	000	8	2/5/2024	NON-COMPETING CONTINUATION	$559,491
2024	2024	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63110	SAINT LOUIS CITY	USA	Research Related to Deafness and Communication Disorders	001	8	5/2/2024	NON-COMPETING CONTINUATION	$62,164
														Subtotal = $621,655

Issue Date FY: 2023 ( Subtotal = $633,045 )
2023	2023	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	000	7	2/17/2023	NON-COMPETING CONTINUATION	$633,045
														Subtotal = $633,045

Issue Date FY: 2022 ( Subtotal = $695,357 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	002	6	7/14/2022	COMPETING CONTINUATION	$6,231
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	000	6	3/10/2022	COMPETING CONTINUATION	$695,357
2022	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	001	5	7/14/2022	NON-COMPETING CONTINUATION	-$6,231
														Subtotal = $695,357

Issue Date FY: 2020 ( Subtotal = $401,577 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	001	5	3/4/2020	NON-COMPETING CONTINUATION	$401,577
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	002	5	5/5/2020	NON-COMPETING CONTINUATION	$0
2020	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	000	4	12/18/2019	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $401,577

Issue Date FY: 2019 ( Subtotal = $774,841 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	001	4	6/17/2019	SUPPLEMENT FOR EXPANSION	$370,214
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	000	4	2/8/2019	NON-COMPETING CONTINUATION	$404,627
														Subtotal = $774,841

Issue Date FY: 2018 ( Subtotal = $406,152 )
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	001	3	4/6/2018	NON-COMPETING CONTINUATION	$40,616
2018	2018	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	000	3	2/20/2018	NON-COMPETING CONTINUATION	$365,536
														Subtotal = $406,152

Issue Date FY: 2017 ( Subtotal = $406,152 )
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	001	2	5/24/2017	NON-COMPETING CONTINUATION	$40,616
2017	2017	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Research Related to Deafness and Communication Disorders	000	2	2/23/2017	NON-COMPETING CONTINUATION	$365,536
														Subtotal = $406,152

Issue Date FY: 2016 ( Subtotal = $462,961 )
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	631121408	SAINT LOUIS CITY	USA	Research Related to Deafness and Communication Disorders	001	1	2/17/2016	NEW	$0
2016	2016	WASHINGTON UNIVERSITY	CAMPUS BOX 1034	SAINT LOUIS	MO	63112	SAINT LOUIS CITY	USA	Research Related to Deafness and Communication Disorders	000	1	2/1/2016	NEW	$462,961
														Subtotal = $462,961

Grand Total All Awards = $4,955,668

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Excitability and Excitotoxicity in Type-I Cochlear Afferents: Synapse Structure and Function

Award Number: R01DC014712

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/10/2016

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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