Tuesday, July 1, 2025 7/1/2025

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: 11/18/2024
PERIOD OF PERFORMANCE END DATE: 10/31/2029

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Internal Dynamics of the Postsynaptic Density - NMDA-type glutamate receptors (NMDARs) shape brain development, synaptic transmission, and disease by acting both as central gatekeepers of synaptic plasticity and as hubs for synaptic protein organization. Strong genetic link between NMDAR subunits and numerous developmental and cognitive disorders places high importance on understanding both the cellular mechanisms that control NMDAR activation and the influence of NMDARs on the synapses where they reside. These receptors are famous as coincidence detectors sensitive to glutamate and postsynaptic voltage, and sensitive to influence at numerous modulatory sites. However, our recent work along with considerable circumstantial evidence from the literature suggests that in fact, activation of these critical receptors is also closely dependent on their subsynaptic positioning and the architecture of the synapse around them. We have found that NMDARs adopt a unique distribution within synapses and are arrayed closely around but offset from just a subset of presynaptic release sites, which modeling predicts will result in high sensitivity to the subsynaptic site of release as well as release probability. Thus, we hypothesize that synapse nanostructure wields strong regulatory control over NMDAR activation. Moreover, our recent work indicates these receptors reciprocally exert direct structural effects on transsynaptic organization. Here, we will dissect this relationship between NMDARs and their synaptic molecular environment. To determine the influence of synaptic nanostructure on receptor activation, we will deploy several information-rich approaches for an unprecedented nanostructure-function investigation of single synapses, including high-throughput optical physiology, post hoc multiplexed nanoimaging, scalable Monte Carlo modeling of these molecularly measured and functionally characterized synapses, and customized machine-learning tools to identify features of synapse protein organization linked to NMDAR signaling. To test directly how the receptors themselves control trans synaptically aligned nanostructure, we will use DNA-PAINT to measure protein organization around and across from NMDARs following knock-in mutagenesis and optical oligomerization, and examine whether these changes help or hinder the induction of plasticity. Finally, recognizing that many aspects of receptor structure remain unknown, particularly in a synaptic context, we here offer a new approach to discern the inner workings of proteins in their native state, and we apply it first to measure the conformational dynamics of NMDARs in synapses. Together, these aims will test multiple new hypotheses about fundamental mechanisms of synapse operation. They will establish a systematic nanostructure-function workflow to link protein abundance and nanostructure to NMDAR-mediated transmission, and generate a new atlas of data-defined synapse subtypes. These aims together offer a deep understanding of one of the most crucial molecules in synaptic transmission, illuminating unexpected cellular mechanisms which control the nature of physiological and pathological plasticity.


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: 11/18/2024

PERIOD OF PERFORMANCE END DATE: 10/31/2029

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