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.

Public Health Relevance

The results from proposed studies will provide evidence that regulation of long-term synaptic plasticity and neurocognitive functions by chronic inactivation of MAGL is mediated via downregulation of the miRNA that targets the molecules important for synaptic integrity. Understanding the mechanism underlying augmentation of 2-AG signaling in regulation of synaptic activity may ultimately lead to effective therapies for the treatment and prevention of mental and neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH113535-02
Application #
9640491
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Nadler, Laurie S
Project Start
2018-02-05
Project End
2019-03-18
Budget Start
2018-12-01
Budget End
2019-03-18
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Louisiana State Univ Hsc New Orleans
Department
Neurosciences
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112