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.
For several decades, mammalian brain cell proliferation and neurogenesis were thought to be restricted to embryonic and early postnatal life, with later brain function relying on the neurons produced during an early developmental window. A different model emerged twenty years ago, with the discovery of two adult stem cell niches in the SVZ of the lateral ventricles and the SGZ of the hippocampus, where neural NSPCs persist and generate new neurons during adult life.(Alvarez-Buylla et al., 2004)(Zhao C. et al, 2008)
Adult neurogenesis decreases with aging and in neuropathological conditions, such as AD, and this may significantly contribute to the cognitive decline observed in the elderly population or in patients affected by neurodegenerative diseases.( Horgusluoglu E. et al. 2017) Despite the potential importance of these findings for human health, the underlying molecular causes of the decline in neurogenesis upon aging or disease are still largely unknown, thus hampering translational approaches aiming at restoring neurogenesis in the aged or the diseased brain.
This study will provide important insight into the role of FAAH-dependent signaling, and of its molecular mechanisms, in NSPCs. In turn, this will help to understand how alteration in FAAH activity and NAE levels may contribute to the cognitive decline associated with aging or neuropathological conditions, and will facilitate the translational use of FAAH inhibitors in studies aimed at preventing or mitigating neurodegeneration during normal or pathological aging.
References:
Alvarez-Buylla A et al. Neuron. 2004;41:683¿686.
Horgusluoglu E. et a. Am J Med Genet B Neuropsychiatr Genet. 2017;174(1):93-112.
Zhao C, Cell. 2008;132:645¿660