# Physiology of Single Synaptic CNS Terminals

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $493,813

## Abstract

Abstract
Mammalian brains are extremely sensitive to metabolic perturbation. If blood glucose drops by only a factor of
~2, immediate neurological symptoms emerge, including delirium and coma. We identified nerve terminals as
a one of the likely loci of this vulnerability, as the vesicle recycling program crashes very quickly upon fuel
withdrawal. We hypothesize that this metabolic sensitivity may lie at the heart of both neurodegenerative and
neuropsychiatric diseases, as brain hypometabolism is a strong predictor of the onset of these diseases
(albeit on different time scales). We seek to address many fundamental knowledge gaps we have
concerning how local synaptic metabolism is regulated, including what molecular machineries for
metabolism support synapse function and how different metabolic fuels can be used to support synapse
function. We recently determined that one of the ten enzymes needed for glycolysis serves as a critical
control point for glycolytic flux in nerve terminals. Enhancing the activity of his enzyme, PGK-1, only 2-fold is
sufficient to provide dramatic protection against hypometabolic synaptic dysfunction. We recently discovered
that synapses contain the necessary machinery to both synthesize and utilize lipid droplets, and that they
normally constantly burn through these lipid droplets to sustain synapse function. Mutations in the key
triglyceride lipase required to lipid droplet use are drivers of neurological disease, including intellectual
disability. Similarly, we have recently uncovered a new role for neuromodulators at nerve terminals: in
addition to directly controlling synapse function, they serve as signals to tell synapses to either store or use
glycogen. Our aims to examine how difference cell biological machineries in synapses allow fuel switching
and how perturbations in these machineries drive or heighten neurological disease states.

## Key facts

- **NIH application ID:** 10815174
- **Project number:** 2R01NS036942-25
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Timothy Aidan Ryan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $493,813
- **Award type:** 2
- **Project period:** 1997-12-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10815174

## Citation

> US National Institutes of Health, RePORTER application 10815174, Physiology of Single Synaptic CNS Terminals (2R01NS036942-25). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10815174. Licensed CC0.

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