# Elucidating the dynamic role of PTPsigma in synaptic nano-organization and NMDA receptor function

> **NIH NIH F31** · UNIVERSITY OF MARYLAND BALTIMORE · 2024 · $43,514

## Abstract

Fine tuning the efficiency of synaptic transmission is essential for learning and memory, while its disruption is
associated with diverse pathologies including autism spectrum disorder, depression, and anxiety disorders.
Thus, identifying mechanisms that regulate synaptic strength is a central goal in neuroscience. Since such
plasticity is frequently triggered by activation of NMDA-type glutamate receptors, understanding the regulation
of NMDA receptors is particularly critical. Recent studies indicate synaptic strength and NMDA receptor
activation can be directly affected by the nanometer-scale organization of proteins within the synapse. Many
synaptic proteins, including vesicle release machinery and postsynaptic scaffolds and receptors, display a
heterogeneous organization with local regions of high protein density, known as nanodomains (NDs). These
NDs can be aligned across the synapse to form a “nanocolumn”, which our lab has demonstrated is the site of
action potential-evoked vesicle fusion and maximal receptor activation. New work from our lab has established
a novel role for the postsynaptic cell-adhesion molecule (CAM) LRRTM2 in positioning AMPA receptors within
the nanocolumn. While CAMs have well-established roles in synapse formation and development, these recent
findings highlight the possibility that CAMs may coordinate synaptic nanostructure and function in the mature
synapse. However, the mechanism by which presynaptic organization and vesicle fusion sites are communicated
to proteins within the postsynaptic density to enable alignment to occur remains unknown. In this proposal I will
investigate whether the presynaptic CAM PTPσ coordinates nanocolumn alignment. PTPσ is important for
synapse formation, is present in the mature synapse, and forms indirect interactions with both pre- and
postsynaptic machinery located within the nanocolumn. Loss of PTPσ impacts both pre- and postsynaptic
physiology, most notably NMDA receptor-mediated responses. Previous attempts to study PTPσ have relied on
chronic manipulations, such as knockouts and knockdowns. However, interpretations are complicated by its
initial role in synapse formation during development. I propose to elucidate the ongoing functions of PTPσ by
acutely disrupting its cleft interactions via cleavage by an exogenous protease. This highly specific and acute
approach will allow me to manipulate PTPσ’s cleft interactions to isolate their functions, without compromising
its earlier role in synapse formation. Throughout this project, I will use super-resolution microscopy,
electrophysiology, molecular biology, and live-cell imaging to test the role of PTPσ cleft interactions in
maintaining nanocolumn alignment and regulating NMDA receptor-mediated transmission. This work will provide
novel insight regarding the roles of a critical family of presynaptic CAMs following development and will test a
new candidate mechanism for the coordination of synaptic nanostructure and NMDA receptor...

## Key facts

- **NIH application ID:** 10868427
- **Project number:** 5F31NS129086-02
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Emily M. DeMarco
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $43,514
- **Award type:** 5
- **Project period:** 2023-05-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868427

## Citation

> US National Institutes of Health, RePORTER application 10868427, Elucidating the dynamic role of PTPsigma in synaptic nano-organization and NMDA receptor function (5F31NS129086-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10868427. Licensed CC0.

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