Ricerc@Sapienza

Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase, highly expressed in the brain and showing elevated levels in several neurological conditions. FAAH catalyzes the degradation of Anandamide (AEA), one of the most characterized endocannabinoids. These molecules play well known roles as synaptic modulators, acting as retrograde inhibitors of neurotransmitter release from pre-synaptic elements. FAAH also hydrolyzes other acylethanolamides (NAEs), including palmitoylethanolamide (PEA), known for its anti-in¿ammatory and neuroprotective properties, and Oleoylethanolamide (OEA), which acts as a fat sensor in regulating energy homeostasis. In rodents, genetic deletion or pharmacological inhibition of FAAH improves memory and extinction learning, and produces anxiolytic, antidepressant and analgesic effects. In mice, a functional endocannabinoid system is present in neural stem/progenitor cells (NSPCs) of the embryonic cortex and of the subventricular and subgranular zones of the adult brain, suggesting a role of endocannabinoids in the regulation of neurogenesis. In this project, we propose to study the effects of FAAH inhibition in NSPCs. To this aim, we will take advantage of in vitro NSPC cultures, chosen as a well-defined experimental system to dissect the mechanism of FAAH function in NSPCs, without the confounding influence of other cell types present in the in vivo brain environment. We plan to evaluate the effects of FAAH inhibition on the viability, proliferation and differentiation of mouse NSPCs from the embryonic cortex and the adult subventricular zone. To this aim, will test both an irreversible and a reversible FAAH inhibitor, namely PF3845 and URB597, two well characterized molecules that are commercially available. This work may allow to gain insight into the molecular mechanisms of NSPC regulation and facilitate the translational use of FAAH inhibitors in neuropathological conditions.