# Endocannabinoid Metabolism and Synaptic Function

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2020 · $385,000

## Abstract

Summary
The long-term goal of this research project is to understand cellular, molecular, and epigenetic mechanisms of
endocannabinoid (eCB) signaling that may modulate synaptic and neurocognitive functions. While the eCB
system is known to play an important role in regulation of brain homeostasis, accumulated information
suggests that the eCB system is also involved in several mental and neurological disorders. Augmentation of
eCB signaling by inhibition of eCB metabolism has been proposed as a promising therapy for treatment and
prevention of mental and neurocognitive illnesses. However, our understanding of the mechanisms underlying
augmentation of eCB signaling by chronic inhibition of eCB metabolism in synaptic activity is still limited.
Strengthening endocannabinoid 2-arachidonoylglycerol (2-AG) signaling by chronic inactivation of
monoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes 2-AG in the brain, has been shown to
produce antidepressant- and anxiolytic-like effects and enhance hippocampal synaptic plasticity as well as
learning and memory. Our recent studies showed that sustained inactivation of MAGL increases the density of
dendritic spines and expression of glutamate receptor subunits in the hippocampus. This suggests that
augmentation of 2-AG signaling by inhibition of MAGL regulates structural and functional plasticity of synapses
that determine activity of neural circuits and corresponding neurocognitive functions. MicroRNAs (miRNAs) are
small noncoding RNAs that negatively regulate expression and function of target molecules. However, we do
not know whether miRNAs that target molecules involved in maintaining the integrity of synaptic structure and
function are regulated by eCB signaling. In the proposed studies, we will test the hypothesis that regulation of
synaptic activity and cognitive function by chronic inactivation of MAGL is through 2-AG signaling-mediated
suppression of the miRNA that targets the molecules important for regulation of synaptic activity. The research
proposed in this application is expected to further our understanding of the mechanisms underlying
augmentation of eCB signaling in regulation of synaptic and neurocognitive functions, which may lead to future
research on improving strategies for the treatment and prevention of mental and neurological illnesses.

## Key facts

- **NIH application ID:** 9823892
- **Project number:** 5R01MH113535-04
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** CHU CHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $385,000
- **Award type:** 5
- **Project period:** 2018-02-05 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9823892

## Citation

> US National Institutes of Health, RePORTER application 9823892, Endocannabinoid Metabolism and Synaptic Function (5R01MH113535-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9823892. Licensed CC0.

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