Tuesday, November 18, 2025 11/18/2025

Internal Dynamics of the Postsynaptic Density

Award Number: R37MH080046
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/05/2007
PERIOD OF PERFORMANCE END DATE: 10/31/2024

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Internal Dynamics of the Postsynaptic Density - Mechanisms that create, maintain, and modulate synapses are essential building blocks of human behavior. Disruptions to these mechanisms are inextricably linked to aberrant behavior and diseases ranging from depression and schizophrenia to addiction and Alzheimer’s Disease. Thus, the long-term goal of this grant is to pursue a deep understanding of the molecular organization underlying synaptic transmission and plasticity. Our previous work took advantage of the extremely high-resolution enabled by single-molecule imaging methods and determined that at glutamatergic synapses, key proteins in the active zone and the postsynaptic density are enriched in subsynaptic nanodomains (<100 nm). Most surprisingly, nanodomains of the critical fusion-regulatory proteins RIM and Munc13 in the presynaptic active zone align with high precision across the synaptic cleft from nanodomains enriched in postsynaptic glutamate receptors. Using single-vesicle fusion mapping, we determined that the local density of RIM within active zone subregions predicts the probability of action potential-evoked vesicle fusion. This striking architectural arrangement has important implications for how synapses function. This nano-alignment between release sites and receptors can modulate synaptic transmission and potentially influence intracellular signaling. Preliminary data here and published work from others establishes that transsynaptic nanoalignment is an important element of synaptic architecture, widely present in diverse synapse types. Further, our data provide firm evidence that subsynaptic nanostructure and nanoalignment are dynamically modulated during synaptic plasticity and actively maintained by ongoing molecular interactions. These observations strongly motivate understanding the mechanisms involved in creating and maintaining transsynaptic alignment. Therefore, we will test a set of related but independent hypotheses about the origin and maintenance of transsynaptic nanoalignment. We will test 1) whether two key neurexin partners, neuroligin and LRRTM, cooperate to provide the structural basis of transsynaptic alignment, 2) whether glutamate receptors themselves are necessary or sufficient to influence the nanoscale protein organization of the active zone 3), whether the active zone RIM complex conveys instructive information to establish postsynaptic nanopatterning, and 4) how the actin cytoskeleton exerts ongoing control over synapse nanoscale architecture. To answer these questions, we have worked to establish and apply several new broadly useful technologies. We utilize a new super-resolution imaging methodology to visualize cellular substructure at nanometer resolution in vivo, apply multiplexed single-molecule imaging to map numerous proteins in the same sample, and develop new optical and biochemical tools to acutely control the actin cytoskeleton, adhesion complexes, and receptor distribution with high spatiotemporal resolution and in brain slices. The outcomes of these experiments will answer core questions about the genesis of an important new aspect of synaptic architecture and test the physiological role of synaptic nanoalignment in brain circuits.


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 = $789,536 )
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	002	18	4/18/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
2025	2025	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	000	18	11/18/2024	EXTENSION WITH OR WITHOUT FUNDS	$789,536
2025	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	001	17	4/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $789,536

Issue Date FY: 2024 ( Subtotal = $685,384 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	000	17	10/19/2023	NON-COMPETING CONTINUATION	$616,848
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	001	17	8/14/2024	NON-COMPETING CONTINUATION	$68,536
														Subtotal = $685,384

Issue Date FY: 2023 ( Subtotal = $681,183 )
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	001	16	2/7/2023	NON-COMPETING CONTINUATION	$68,118
2023	2023	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	000	16	12/15/2022	NON-COMPETING CONTINUATION	$613,065
														Subtotal = $681,183

Issue Date FY: 2022 ( Subtotal = $714,476 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	000	15	11/1/2021	NON-COMPETING CONTINUATION	$643,029
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	001	15	6/26/2022	NON-COMPETING CONTINUATION	$71,447
														Subtotal = $714,476

Issue Date FY: 2021 ( Subtotal = $712,430 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	000	14	10/29/2020	NON-COMPETING CONTINUATION	$641,187
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	001	14	4/21/2021	NON-COMPETING CONTINUATION	$71,243
														Subtotal = $712,430

Issue Date FY: 2020 ( Subtotal = $877,279 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	002	13	5/11/2020	COMPETING CONTINUATION	$163,973
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	000	13	12/20/2019	COMPETING CONTINUATION	$644,698
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Mental Health Research Grants	001	13	2/22/2020	COMPETING CONTINUATION	$68,608
														Subtotal = $877,279

Grand Total All Awards = $4,460,288

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Internal Dynamics of the Postsynaptic Density

Award Number: R37MH080046

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/05/2007

PERIOD OF PERFORMANCE END DATE: 10/31/2024

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