# Trans-synaptic control of presynaptic neurotransmitter release

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $418,879

## Abstract

Dysfunction in mechanisms that regulate the development, maintenance, and plasticity of synaptic connections
have been linked to many neuropsychiatric and neurodevelopmental disorders, and thus a deep molecular understanding of these processes will be crucial in relieving the severe health burden these disorders impose.
One aspect of synaptic communication that is critical for information processing in the brain is the maintenance
of precise functional alignment between presynaptic neurotransmitter release and postsynaptic function at individual synapses, but the local signals that control this aspect of “synaptic homeostasis” are poorly understood.
This project will focus on a recently discovered homeostatic pathway in hippocampal neurons that functions to
tune presynaptic neurotransmitter release when postsynaptic receptor activation is deficient. My laboratory
has recently described a unique homeostatic signaling pathway that couples synaptic inactivity to mTOR complex 1 (mTORC1) signaling in postsynaptic dendrites. mTORC1 activation, in turn, drives the local dendritic
translation and release of brain-derived neurotrophic factor (BDNF), which elicits compensatory increases in
neurotransmitter release from apposed presynaptic terminals but only if those terminals have been recently
active. This state-dependent gating of synaptic homeostasis by local presynaptic activity ensures coupling of
mTORC1 trans-synaptic signaling to spike-driven neurotransmitter release. During the previous period of support, we discovered that BDNF elicits presynaptic compensation via the proteasome-dependent degradation of
the synaptic regulator tomosyn1 (Tomo1), which is catalyzed by the E3 ubiquitin ligase HRD1. During these
investigations, we uncovered an unexpected and critical role for activity-dependent recruitment of the proteasome to axonal boutons. We now propose to test the central hypothesis that activity-dependent sequestration of proteasomes in presynaptic terminals confers state-dependent gating of synaptic homeostasis driven by
postsynaptic mTORC1 signaling. Our investigations will examine how regulated phosphorylation of the 19S
proteasome subunit Rpt6 dynamically regulates proteasome distribution in axons (Aim 1), define the core signaling pathway in axon terminals that links neural activity (and specifically, P/Q/N voltage-gated Ca2+ channel
activity) with posttranslational modifications of the proteasome important for synaptic targeting (Aim 2), and
define the molecular mechanisms that control proteasome sequestration in axon terminals (Aim 3). In each of
these aims, the relationship of the mechanisms uncovered with mTORC1 trans-synaptic homeostatic signaling
will be rigorously tested. The proposed experiments employ state of the art optical imaging of synaptic vesicle
cycling and release, genetic models targeting mTORC1 signaling and proteasome phosphorylation, rigorous
electrophysiological measurements, and are focused on a fundamentally new area...

## Key facts

- **NIH application ID:** 10754243
- **Project number:** 5R01NS097498-08
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Michael Mark Alexander Sutton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $418,879
- **Award type:** 5
- **Project period:** 2016-06-15 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754243

## Citation

> US National Institutes of Health, RePORTER application 10754243, Trans-synaptic control of presynaptic neurotransmitter release (5R01NS097498-08). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10754243. Licensed CC0.

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