ENDOCANNABINOID METABOLISM AND SYNAPTIC FUNCTION

The long-term goal of this research project is to understand cellular, molecular, and epigenetic mechanisms ofendocannabinoid (eCB) signaling that may modulate synaptic and neurocognitive functions. While the eCBsystem is known to play an important role in regulation of brain homeostasis, accumulated informationsuggests that the eCB system is also involved in several mental and neurological disorders. Augmentation ofeCB signaling by inhibition of eCB metabolism has been proposed as a promising therapy for treatment andprevention of mental and neurocognitive illnesses. However, our understanding of the mechanisms underlyingaugmentation 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 ofmonoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes 2-AG in the brain, has been shown toproduce antidepressant- and anxiolytic-like effects and enhance hippocampal synaptic plasticity as well aslearning and memory. Our recent studies showed that sustained inactivation of MAGL increases the density ofdendritic spines and expression of glutamate receptor subunits in the hippocampus. This suggests thataugmentation of 2-AG signaling by inhibition of MAGL regulates structural and functional plasticity of synapsesthat determine activity of neural circuits and corresponding neurocognitive functions. MicroRNAs (miRNAs) aresmall noncoding RNAs that negatively regulate expression and function of target molecules. However, we donot know whether miRNAs that target molecules involved in maintaining the integrity of synaptic structure andfunction are regulated by eCB signaling. In the proposed studies, we will test the hypothesis that regulation ofsynaptic activity and cognitive function by chronic inactivation of MAGL is through 2-AG signaling-mediatedsuppression of the miRNA that targets the molecules important for regulation of synaptic activity. The researchproposed in this application is expected to further our understanding of the mechanisms underlyingaugmentation of eCB signaling in regulation of synaptic and neurocognitive functions, which may lead to futureresearch on improving strategies for the treatment and prevention of mental and neurological illnesses.