Friday, April 26, 2024 4/26/2024

Molecular Mechanisms Governing the Homeostatic Control of Synaptic Strength

Award Number: R01NS091546
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

Group Awards By Issue Date FY or Funding FY:

View Award Abstract

Homeostatic signaling systems operate at synapses to enable flexible yet stable information transfer in the nervous system. Defects in homeostatic signaling contribute to seizures, excitotoxicity, cognitive decline, and neurodegeneration. Although much has been learned in recent years about the expression mechanisms synapses employ to counteract perturbations to neurotransmission, the pathways that rapidly initiate and chronically maintain homeostatic signaling remains poorly understood. Here, we propose to determine the induction mechanisms mediating homeostatic synaptic plasticity using the Drosophila neuromuscular junction as a unique and powerful model system. At this glutamatergic synapse, pharmacologic or genetic disruption to postsynaptic neurotransmitter receptors triggers a retrograde signaling system that leads to a compensatory increase in presynaptic glutamate release to maintain stable synaptic strength, referred to as presynaptic homeostatic potentiation (PHP). This process parallels similar phenomena observed in a variety of other organisms, including mammalian central synapses. We have recently discovered an E3 ubiquitin ligase adaptor that targets substrates in the postsynaptic compartment and enables retrograde homeostatic signaling. We propose to first identify and characterize postsynaptic targets of the homeostatic signaling system. Preliminary data suggests a key component of the postsynaptic density is necessary for retrograde homeostatic signaling. Next, we will define the induction mechanisms mediating the chronic expression of PHP and determine the role of CaMKII in this process. Finally, we will interrogate the pharmacological induction of PHP and test a hypothesis that trans-synaptic complexes mediate rapid retrograde homeostatic signaling. These studies will leverage a synergistic combination of molecular genetic, electrophysiological, and innovative functional imaging approaches at confocal, super resolution, and ultrastructural levels to determine the induction mechanisms that initiate and maintain retrograde homeostatic signaling. Together, these experiments will advance our understanding of the fundamental mechanisms that endow synapses with the capacity to sense perturbations to neurotransmission and adaptively modulate synaptic function to stabilize information transfer in the nervous system.


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 = $422,599 )
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	10	4/11/2024	NON-COMPETING CONTINUATION	$25,177
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	10	1/19/2024	NON-COMPETING CONTINUATION	$323,721
2024	2024	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	10	1/23/2024	SUPPLEMENT FOR EXPANSION	$73,701
														Subtotal = $422,599

Issue Date FY: 2023 ( Subtotal = $433,390 )
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	9	1/9/2023	NON-COMPETING CONTINUATION	$323,721
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	9	1/31/2023	NON-COMPETING CONTINUATION	$35,968
2023	2023	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	9	1/10/2023	SUPPLEMENT FOR EXPANSION	$73,701
														Subtotal = $433,390

Issue Date FY: 2022 ( Subtotal = $433,390 )
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	8	12/10/2021	NON-COMPETING CONTINUATION	$323,720
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	8	3/28/2022	NON-COMPETING CONTINUATION	$35,969
2022	2022	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	8	1/17/2022	SUPPLEMENT FOR EXPANSION	$73,701
														Subtotal = $433,390

Issue Date FY: 2021 ( Subtotal = $472,026 )
2021	2021	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	7	1/27/2021	NON-COMPETING CONTINUATION	$475,237
2021	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	1/26/2021	SUPPLEMENT FOR EXPANSION	-$3,211
														Subtotal = $472,026

Issue Date FY: 2020 ( Subtotal = $483,688 )
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	6	6/24/2020	COMPETING CONTINUATION	$1,054
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	11/20/2019	COMPETING CONTINUATION	$369,419
2020	2020	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	6	1/22/2020	SUPPLEMENT FOR EXPANSION	$114,269
2020	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	5	6/24/2020	NON-COMPETING CONTINUATION	-$1,054
														Subtotal = $483,688

Issue Date FY: 2019 ( Subtotal = $369,539 )
2019	2019	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90007	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	12/20/2018	NON-COMPETING CONTINUATION	$369,539
														Subtotal = $369,539

Issue Date FY: 2018 ( Subtotal = $467,462 )
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	1/12/2018	NON-COMPETING CONTINUATION	$420,715
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	1/18/2018	NON-COMPETING CONTINUATION	$0
2018	2018	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	5/21/2018	NON-COMPETING CONTINUATION	$46,747
														Subtotal = $467,462

Issue Date FY: 2017 ( Subtotal = $458,861 )
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	4/19/2017	SUPPLEMENT FOR EXPANSION	$12,948
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	1/11/2017	NON-COMPETING CONTINUATION	$324,844
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	3	6/8/2017	NON-COMPETING CONTINUATION	$36,094
2017	2017	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER STREET THIRD FLOOR	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	1/13/2017	SUPPLEMENT FOR EXPANSION	$84,975
														Subtotal = $458,861

Issue Date FY: 2016 ( Subtotal = $360,938 )
2016	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	1/25/2016	NON-COMPETING CONTINUATION	$36,094
2016	2016	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	12/15/2015	NON-COMPETING CONTINUATION	$324,844
														Subtotal = $360,938

Issue Date FY: 2015 ( Subtotal = $360,482 )
2015	2015	UNIVERSITY OF SOUTHERN CALIFORNIA	3500 SOUTH FIGUEROA STREET 102	LOS ANGELES	CA	90089	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	1/30/2015	NEW	$360,482
														Subtotal = $360,482

Grand Total All Awards = $4,262,375

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Molecular Mechanisms Governing the Homeostatic Control of Synaptic Strength

Award Number: R01NS091546

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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