# Activity-dependent degradation of a neuromodulator

> **NIH NIH R01** · LSU HEALTH SCIENCES CENTER · 2021 · $405,412

## Abstract

Neuromodulators control both synaptic transmission and the intrinsic excitability of neurons and are essential
for CNS function. Most studies of neuroplasticity have focused on the regulation of neuromodulator synthesis
or the receptors through which they signal. In contrast, the enzymatic degradation of these compounds has
received less attention even though this controls the temporal profile of their modulatory action. This is
surprising given the therapeutic potential of regulating the rate of degradation. For example inhibition of
endocannabinoid degradation can reduce anxiety-like behaviors in rodents. In theory, an activity-dependent
change in degradation would be expected to alter local neuromodulator levels and provide a powerful
mechanism to regulate the activity of an entire neuronal circuit. Surprisingly studies of physiological regulation
of degradation have lagged compared to its use clinically. We propose that neuronal activity can regulate the
degradation of a neuromodulator, endocannabinoids. Endocannabinoids such as 2-AG, are released when
neurons are activated (“on-demand”) and suppress neurotransmitter release and intrinsic excitability. MAGL
(Monoacylglycerol lipase), a 2-AG degrading enzyme, terminates their activity and this process can be altered
by experience because the level of MAGL changes following stress and alcohol abuse. In this application, we
propose to investigate whether neuronal activity can regulate the degradation of 2-AG in the cerebellum, a
brain region critical for motor control and associative fear memory formation. While searching for a
physiological stimulus that could activate this pathway we found that fear conditioning can elevate both MAGL
levels and 2-AG degradation, and furthermore these effects were blocked by administration of a PPARα
inhibitor. We therefore propose that PPARα acts as a master regulator of MAGL/2-AG signaling, in that it
couples a change in neuronal activity to a change in 2-AG degradation. Our central hypothesis is that
neuronal activity upregulates 2-AG degradation via a PPARα-dependent pathway and thereby
increases the activity of this cerebellar circuit. In aim 1 we will test whether neuronal activity induces a
lasting increase in MAGL and 2-AG degradation via a PPARα-dependent pathway. In aim 2 we will determine
whether fear learning elevates 2-AG degradation via a PPARα-MAGL dependent pathway and alters the
activity of a cerebellar circuit. Investigation of how neuronal activity regulates endocannabinoid degradation is
fundamental to our understanding of neuronal plasticity at the circuit level. If we can confirm a role for PPARα
in an activity-dependent increase in MAGL expression this may allow us to selectively prevent, or facilitate,
MAGL-dependent plasticity without affecting the basal level of this enzyme. This could provide a distinct
therapeutic advantage over inhibitors of MAGL which elevate 2-AG levels and can lead to functional
desensitization of the endocannabi...

## Key facts

- **NIH application ID:** 10189725
- **Project number:** 5R01NS106915-03
- **Recipient organization:** LSU HEALTH SCIENCES CENTER
- **Principal Investigator:** Siqiong June Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $405,412
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10189725

## Citation

> US National Institutes of Health, RePORTER application 10189725, Activity-dependent degradation of a neuromodulator (5R01NS106915-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10189725. Licensed CC0.

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