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Shedding light on balance: Interrogating individual synapses within vestibular epithelia

Award Number: R21DC020581
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary The present application proposes a developmental research plan to investigate the structure-function relationship of individual presynaptic complexes in mammalian vestibular hair cells. These complexes incorporate synaptic ribbons that can exhibit broad architectural heterogeneity, the functional significance of which is not known. The distribution of presynaptic architectures in the primary hair cell phenotypes (i.e. types I and II) within vestibular epithelia, and the unique dendritic specialization known as the calyx (encapsulating type I hair cells), render traditional methods of investigating synaptic function inappropriate for elucidating the functional characteristics of individual synaptic sites. Recent advances in the development of optical biosensors and viral transduction strategies provide the foundation for novel capabilities to detect and quantify neurotransmitter release at individual synapses. iGluSnFR is a genetically encoded, membrane bound glutamate sensor. When expressed at the postsynaptic membrane, it emits a fluorescent signal proportional to glutamate release. Recent key investigations demonstrated that when packaged with an AAV9 capsid and a synapsin promoter, inner ear afferent neurons are transduced and iGluSnFR is expressed. This strategy directs the sensor to the appropriate postsynaptic targets for measuring glutamate release from individual hair cell synapses. When coupled with strategies for post-recording elucidation of synaptic ribbons an association between glutamate release and synapse structure can be made. The project includes three Aims to: 1) optimize transduction in vestibular afferent neurons; 2) develop and optimize recording strategies to capture the time- resolved glutamate release from individual synaptic sites; and 3) evaluate the methods in a mouse model for which presynaptic function in type I hair cells is drastically attenuated. Immunohistochemical processing following optical recording will enable the direct association of immunolabeled ribbons with the recording sites, for which ribbon volume provides a proxy of its architecture. The development of these methods provides the foundation future studies of pathologic conditions whose etiologies are proposed to involve synaptopathies. This investigation will enable future investigations of synaptic function in normal and pathologic conditions, and provide a platform for the rigorous evaluation of novel treatments of inner ear dysfunction.


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: 2024 ( Subtotal = $195,000 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Research Related to Deafness and Communication Disorders	000	2	8/13/2024	NON-COMPETING CONTINUATION	$195,000
														Subtotal = $195,000

Issue Date FY: 2023 ( Subtotal = $234,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Research Related to Deafness and Communication Disorders	000	1	12/14/2022	NEW	$234,000
														Subtotal = $234,000

Grand Total All Awards = $429,000

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Shedding light on balance: Interrogating individual synapses within vestibular epithelia

Award Number: R21DC020581

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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