# Evaluating the functional impact of synaptic nanoarchitecture

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $525,700

## Abstract

Summary
Numerous brain disorders and diseases are caused by deficits in synapse function. Synaptic
transmission is traditionally thought to be governed by the amount of neurotransmitter released and the
number of neurotransmitter receptors localized to the postsynaptic membrane. However, accumulating
evidence suggests synaptic function not only depends on the number of postsynaptic receptors, but also
their precise nanoscale positioning within the postsynaptic membrane. For example, at excitatory
synapses AMPA-type glutamate receptors (AMPARs) form one or more clustered sub-structures within
the postsynaptic density that are precisely aligned with presynaptic neurotransmitter release sites.
Modeling studies predict this pre/post alignment to be critical for efficient AMPAR activation, but this has
been challenging to address experimentally. The degree to which receptor nano-positioning influences
synaptic function remains unclear due to a lack of suitable approaches for 1. Rapid and reversible
perturbations to synaptic nanostructure that allow simultaneous synaptic function measurements. 2.
Probing glutamate concentrations directly within distinct synaptic nanodomains. 3. Testing the functional
relationship between receptor activation and distance from neurotransmitter release sites. To address
these issues, we have recently developed new approaches for rapidly manipulating postsynaptic
scaffolds and receptors in real time. In parallel we have developed a new set of genetically encoded
affinity reagents for labeling and manipulating endogenous AMPARs. We propose to combine these
approaches to assess the functional relevance and regulation of nano-scale positioning within the PSD, a
problem that has been challenging to assess using conventional approaches.

## Key facts

- **NIH application ID:** 10779077
- **Project number:** 1R01MH134957-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Matthew J Kennedy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $525,700
- **Award type:** 1
- **Project period:** 2024-01-01 → 2028-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10779077

## Citation

> US National Institutes of Health, RePORTER application 10779077, Evaluating the functional impact of synaptic nanoarchitecture (1R01MH134957-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10779077. Licensed CC0.

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