Abstract
Endocannabinoid synthesis in the human body is naturally occurring and on-demand. It occurs in response to physiological and environmental stimuli, such as stress, anxiety, hunger, other factors negatively disrupting homeostasis, as well as the therapeutic use of the phytocannabinoid cannabidiol and recreational use of exogenous cannabis, which can lead to cannabis use disorder. Together with their specific receptors CB1R and CB2R, endocannabinoids are major components of endocannabinoid-mediated neuromodulation in a rapid and sustained manner. Extensive research on endocannabinoid function and expression includes studies in limbic system structures such as the hippocampus and amygdala. The wide distribution of endocannabinoids, their on-demand synthesis at widely different sites, their co-existence in specific regions of the body, their quantitative differences in tissue type, and different pathological conditions indicate their diverse biological functions that utilize specific and overlapping pathways in multiple organ systems. Here, we review emerging evidence of these pathways with a special emphasis on the role of endocannabinoids in decelerating neurodegenerative pathology through neural networks initiated by cells in the main olfactory bulb.
Highlights
The endocannabinoid system is a unique system of neuromodulation that has been characterized mainly in the last thirty years starting with the identification of its main and associated receptor components, ligands, agonists, antagonists, participating in synthesis and degradation, cofactors, transporter proteins, activating and inhibitory cytoskeletal components, transcription factors and their modifiers [1,2,3]
Based on site-specific on-demand synthesis in many tissues and the involvement of multiple cell types where retrograde messenger activity affects synaptic plasticity, there is a surge of research activity to identify endocannabinoid functions in neurodegenerative diseases in a bidirectional approach: first, in disrupting the progression of symptoms of neurodegenerative pathology and second, in applying therapeutic intervention/s to modify erratic behavioral patterns that may emerge as consequence of progressing neurodegenerative pathology
We have summarized many studies that indicate an on-demand endocannabinoid system response in multiple tissues to a range of stimuli affecting widely different biological functions
Summary
The endocannabinoid system is a unique system of neuromodulation that has been characterized mainly in the last thirty years starting with the identification of its main and associated receptor components, ligands, agonists, antagonists, participating in synthesis and degradation, cofactors, transporter proteins, activating and inhibitory cytoskeletal components, transcription factors and their modifiers [1,2,3]. Despite the detection of cannabinoid type 1 receptor (CB1R) and cannabinoid type 2 receptor (CB2R) mRNA and protein in the olfactory epithelium, olfactory-mediated behavior remained normal in knockout mouse models of these receptors [19] These findings suggest that the olfactory bulb is a site of synaptic plasticity with a functional role of the endocannabinoid system. Whereas cell type specific CB2R protein expression remained ambiguous due to non-specific antibodies, it is evident by immunoblot, possibly due to CB2R expressing immune cells in the lamina propria [19] These findings have established olfactory bulb cell layers as a dynamic site for modulation of molecular signaling at the single cell level throughout the lifetime of an organism. Our goal is to better understand how the signaling machinery in olfactory cell layers reacts to on-demand endocannabinoid system responses, to identify relevant pathways that contribute to neurodegenerative pathology, and to provide additional entry points to explore therapeutic intervention at the level of synaptic signaling
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