Wednesday, February 18, 2026 2/18/2026

Generating functional diversity from molecular homogeneity at glutamatergic synapses

Award Number: R01NS126654
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Generating functional diversity from molecular homogeneity at glutamatergic synapses - PROJECT SUMMARY Synapses are fundamental units of communication in the nervous system, where immense diversity in structure and function serve to tune and calibrate information transfer. Defects in the ability of synapses to properly diversify contribute to the etiology of a variety of neurodevelopmental, psychiatric, and neurodegenerative diseases. One means of generating diversity in synaptic function is through molecular heterogeneity, where combinations of distinct genes are expressed at individual synapses to enable specific functional properties. However, it has become increasingly clear, though difficult to resolve, that remarkable synaptic diversity can be achieved from a limited set of molecular machinery. In principle, the Drosophila neuromuscular junction (NMJ) is a uniquely powerful model to address how synaptic diversity is generated given the sophisticated genetic, electrophysiological, and imaging approaches. In this system, two distinct motor neurons converge to co-innervate individual muscle targets, where transmission from a strong and weak input together drive muscle contraction in the motor circuit. However, an inability to selectively isolate transmission from either input has been a major limitation towards understanding synaptic diversity in this system. Here, we propose to use expression of a unique Botulinum NeuroToxin (BoNT) to selectively silence transmission at strong or weak synaptic inputs. Preliminary data suggests that while each neuron is largely composed of the same molecular machinery at active zones, one core component, previously thought to function universally at all active zones, actually subserves dramatically different roles at strong vs weak synapses. We will use BoNT silencing, super resolution imaging, and the latest calcium reporters targeted to release sites to illuminate differences in active zone nanostructure and function between strong and weak synapses. We will also leverage new innovations in CRISPR mutagenesis to dissect the specialized functions of eight core active zone components at strong vs weak synapses. Finally, we will interrogate how these core active zone components are uniquely targeted for modulation and remodeling at strong vs weak synapses in the context of homeostatic synaptic plasticity. Together, these approaches will unlock fundamental insights into how glutamatergic synaptic diversity is established and adaptively modified through plasticity. Ultimately, this understanding will illuminate key mechanisms through which heterogeneous functional properties at glutamatergic release sites are enabled by a limited molecular toolkit.


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: 2026 ( Subtotal = $346,389 )
2026	2026	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	12/23/2025	NON-COMPETING CONTINUATION	$346,389
														Subtotal = $346,389

Issue Date FY: 2025 ( Subtotal = $465,560 )
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	11/21/2024	NON-COMPETING CONTINUATION	$354,619
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	11/22/2024	SUPPLEMENT FOR EXPANSION	$37,901
2025	2025	UNIVERSITY OF SOUTHERN CALIFORNIA	3720 S FLOWER ST FL 3	LOS ANGELES	CA	90033	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	11/26/2024	SUPPLEMENT FOR EXPANSION	$73,040
														Subtotal = $465,560

Issue Date FY: 2024 ( Subtotal = $488,754 )
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	003	2	4/29/2024	SUPPLEMENT FOR EXPANSION	$50,869
2024	2024	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	2	12/1/2023	NON-COMPETING CONTINUATION	$339,958
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	2	4/24/2024	NON-COMPETING CONTINUATION	$26,440
2024	2024	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	2	12/11/2023	SUPPLEMENT FOR EXPANSION	$71,487
														Subtotal = $488,754

Issue Date FY: 2023 ( Subtotal = $428,233 )
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	1	11/29/2022	NEW	$380,491
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	1	6/29/2023	SUPPLEMENT FOR EXPANSION	$33,610
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	1	12/2/2022	NEW	$14,132
														Subtotal = $428,233

Grand Total All Awards = $1,728,936

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Generating functional diversity from molecular homogeneity at glutamatergic synapses

Award Number: R01NS126654

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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