# Molecular and Synaptic Mechanisms of Neurotrophin-glutamate Crosstalk

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $526,214

## Abstract

PROJECT SUMMARY
Synaptic transmission and its plasticity are based on a core group of synaptic receptors that rapidly sense
neurotransmitters such as glutamate and GABA. Neurotrophins, such as brain-derived neurotrophic factor
(BDNF), are typically thought to signal on slower time scales, but have also been shown to regulate the induction
and expression of synaptic plasticity. Despite both neurotransmitter and neurotrophin signaling underlying most
forms of synaptic plasticity and serving as major mediators of the pathophysiology and treatment of
neurogenerative and neuropsychiatric disorders, little is known about how these different receptor classes work
in concert through direct and indirect forms of crosstalk. Motivated by the paucity of direct tests of
neurotrophin/neurotransmitter crosstalk, our preliminary studies have indicated that the neurotrophin receptor,
TrkB, and metabotropic glutamate receptor 5 (mGluR5) are able to mutually regulate each other in both native
and heterologous systems. In contrast to previous studies which have focused on the ability of GPCRs to activate
RTK signaling, we have identified one of the first examples of an RTK (TrkB) engaging a GPCR (mGluR5) as a
signaling effector. In this proposal, we will test the hypothesis that mGluR5 is a critical mediator of TrkB effects
by amplifying and altering the spatiotemporal dynamics of downstream signaling to canonical effectors to drive
a unique form of crosstalk-dependent synaptic plasticity. Collectively, this new form of TrkB-mGluR5 signaling
may contribute to the diverse higher order nervous system functions related to neural plasticity that have been
attributed to the BDNF-TrkB neurotrophin system. Aim 1 will define BDNF-TrkB receptor mediated signaling
crosstalk with mGluR5. Aim 2 will decipher the signaling mechanisms that regulate TrkB/mGluR5 crosstalk. Aim
3 will determine the impact of TrkB-mGluR5 synergy on BDNF-LTP and mGluR5-LTD.

## Key facts

- **NIH application ID:** 10907627
- **Project number:** 5R01NS126590-03
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Francis Sang Yong Lee
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $526,214
- **Award type:** 5
- **Project period:** 2022-09-28 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10907627

## Citation

> US National Institutes of Health, RePORTER application 10907627, Molecular and Synaptic Mechanisms of Neurotrophin-glutamate Crosstalk (5R01NS126590-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10907627. Licensed CC0.

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