Genetic Manipulation of the Endocannabinoid System

Abstract

The physiological and pathophysiological functions of the endocannabinoid system have been studied extensively using transgenic and targeted knockout mouse models. The first gene deletions of the cannabinoid CB(1) receptor were described in the late 1990s, soon followed by CB(2) and FAAH mutations in early 2000. These mouse models helped to elucidate the fundamental role of endocannabinoids as retrograde transmitters in the CNS and in the discovery of many unexpected endocannabinoid functions, for example, in the skin, bone and liver. We now have knockout mouse models for almost every receptor and enzyme of the endocannabinoid system. Conditional mutant mice were mostly developed for the CB(1) receptor, which is widely expressed on many different neurons, astrocytes and microglia, as well as on many cells outside the CNS. These mouse strains include "floxed" CB(1) alleles and mice with a conditional re-expression of CB(1). The availability of these mice made it possible to decipher the function of CB(1) in specific neuronal circuits and cell populations or to discriminate between central and peripheral effects. Many of the genetic mouse models were also used in combination with viral expression systems. The purpose of this review is to provide a comprehensive overview of the existing genetic models and to summarize some of the most important discoveries that were made with these animals.

THC Treatment Alters Glutamate Receptor Gene Expression in Human Stem Cell-Derived Neurons

“…Evidence from neuron subtype-specific deletions suggests that CB1R may have different functions and pharmacological properties in different cell types (reviewed in [17]) and that its subcellular localization may mediate distinct signaling [18,19]. Endocannabinoids play critical roles during fetal brain development, being involved in neuronal differentiation, survival and the regulation of neurotransmitter systems [20,21,22].…”

Cannabinoid Control of Olfactory Processes: The Where Matters

“…Instead, Hutch and colleagues [27] investigated the involvement of CB1 receptors in olfactory-mediated learning and memory tasks such as the buried food test and a habituation/dishabituation paradigm. In addition, CB1-KO mice lack brain specificity and might be confounded by compensatory mechanisms [49]. Thus, the physiological role of CB1 receptors in the mammalian OE still remains unclear and will need further investigation.…”

Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years

“…Studies performed on these allelic variants highlighted a different susceptibility to drug/alcohol abuse (Sipe et al, 2002; Chiang et al, 2004; Zhou et al, 2016), supporting a potential link between functional abnormalities in eCB signaling and drug/alcohol dependance. This is just an example of the potential impact of genetic manipulation of eCB system on human health (Zimmer, 2015), for instance on the widespread cannabis use disorder (Boileau et al, 2016). In addition, accumulating evidence points to AEA as a unique natural repressor of gene transcription, via epigenetic mechanisms that include increased DNA methylation (Paradisi et al, 2008), reduced histone acetylation and microRNA (D’Addario et al, 2013).…”