# Glutamate receptor mediated organization of synaptic nanostructure

> **NIH NIH F31** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $37,486

## Abstract

Fine tuning of glutamatergic synaptic transmission underlies information processing in the brain. Exquisite
regulatory control arises from subsynaptic protein organization at the nanometer scale. Though key aspects of
molecular organization within the active zone and postsynaptic density are well known, our lab recently reported
a novel coordination of nanoscale organization between pre- and postsynaptic specializations at the synapse.
Clusters of proteins establishing presynaptic sites of action potential-evoked neurotransmitter release
(particularly RIM1/2) are aligned across the synapse with postsynaptic nanoclusters of glutamate receptors and
scaffold proteins such as PSD-95. This alignment is spatially confined to ~80 nm in diameter, much smaller than
the size of the entire synapse. This `nanocolumn' organization is expected to increase synaptic strength by
enhancing the probability of receptor activation during synaptic transmission (Tang et al., 2016), and may reveal
a modular structure important for synaptic plasticity. Thus, understanding the biology governing this trans-
synaptic alignment could prove useful for our understanding of diseases and disorders in which synaptic
transmission is known to be disrupted, including schizophrenia and autism spectrum disorders. Nevertheless,
the mechanism by which this trans-cellular alignment is established is unknown. One unexplored explanation
with important implications for synaptic function involves the glutamate receptors themselves. AMPA receptors
and NMDA receptors are arranged in nanoclusters and are enriched within the nanocolumn. Furthermore, they
interact with PSD-95 intracellularly and their large extracellular domains are known to bind numerous trans-
synaptic proteins found in the synaptic cleft. Given these observations, I hypothesize that glutamate receptors
mediate trans-synaptic alignment of RIM1/2 and PSD-95 nanoclusters. To test this, I first will use established
mouse lines as well as knockdown experiments in culture to examine the protein distribution of synapses entirely
lacking in ionotropic glutamate receptors. I will conduct three dimensional direct stochastic optical reconstruction
microscopy (3D dSTORM) and expansion microscopy to assess trans-synaptic alignment, and whole-cell patch
clamp electrophysiology to validate the loss of AMPA and NMDA currents. Should alignment be disturbed, I will
then explore which glutamate receptors are responsible for alignment. Second, I will test whether receptor
position within the synapse is sufficient to dictate presynaptic protein organization. To do this, I will use a
published optical dimerization technique to recruit glutamate receptors to both central and peripheral sites within
the postsynaptic density. Following recruitment, I will use 3D dSTORM to determine if alignment of RIM1/2
nanoclusters is dependent on positioning of recruited receptors. Glutamate receptors, though obviously critical
for synaptic transmission, are often ...

## Key facts

- **NIH application ID:** 9792264
- **Project number:** 5F31MH117920-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Poorna Akalanka Dharmasri
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,486
- **Award type:** 5
- **Project period:** 2018-12-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9792264

## Citation

> US National Institutes of Health, RePORTER application 9792264, Glutamate receptor mediated organization of synaptic nanostructure (5F31MH117920-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9792264. Licensed CC0.

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