# Internal Dynamics of the Postsynaptic Density

> **NIH NIH R37** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $712,430

## Abstract

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 outco...

## Key facts

- **NIH application ID:** 10075978
- **Project number:** 5R37MH080046-14
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Thomas A Blanpied
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $712,430
- **Award type:** 5
- **Project period:** 2007-04-05 → 2024-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10075978

## Citation

> US National Institutes of Health, RePORTER application 10075978, Internal Dynamics of the Postsynaptic Density (5R37MH080046-14). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10075978. Licensed CC0.

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