The Role of Endocannabinoid Signaling in Cortical Inhibitory Neuron Dysfunction in Schizophrenia

Abstract

Cannabis use has been reported to increase the risk of developing schizophrenia and to worsen symptoms of the illness. Both of these outcomes might be attributable to the disruption by cannabis of the endogenous cannabinoid system's spatiotemporal regulation of the inhibitory circuitry in the prefrontal cortex that is essential for core cognitive processes, such as working memory, which are impaired in schizophrenia. In the healthy brain, the endocannabinoid 2-arachidonylglycerol (2-AG) is 1) synthesized by diacylglycerol lipase in pyramidal neurons; 2) travels retrogradely to nearby inhibitory axon terminals that express the primary cannabinoid receptor CB1R; 3) binds to CB1R which inhibits GABA release from the cholecystokinin-containing population of interneurons; and 4) is metabolized by either monoglyceride lipase, which is located in the inhibitory axon terminal, or by α-β-hydrolase domain 6, which is co-localized presynaptically with diacylglycerol lipase. Investigations of the endogenous cannabinoid system in the prefrontal cortex of subjects with schizophrenia have found evidence of higher metabolism of 2-AG, as well as both greater CB1R receptor binding and lower levels of CB1R mRNA and protein. Current views on the potential pathogenesis of these alterations, including disturbances in the development of the endogenous cannabinoid system, are discussed. In addition, how interactions between these alterations in the endocannabinoid system and those in other inhibitory neurons in the prefrontal cortex in subjects with schizophrenia might increase the liability to adverse outcomes with cannabis use is considered.

Long-term hippocampal interneuronopathy drives sex-dimorphic spatial memory impairment induced by prenatal THC exposure

“…Hence, both perinatal and adolescent exposure to cannabinoids result in GABAergic hypofunction. The contribution of this GABAergic hypofunction to the neuropsychiatric traits induced by developmental cannabinoid exposure has been mainly associated to increased risk of developing psychosis or schizophrenia [37]. Alternatively, cannabinoid-induced remodeling and plasticity of GABAergic circuits can contribute to cognitive impairment [38].…”

Seeing through the smoke: Human and animal studies of cannabis use and endocannabinoid signalling in corticolimbic networks

“…blunted affect, social withdrawal) symptomology (Hajos and Freund, 2002; Nguyen et al, 2014). Literature concerning the role of endocannabinoid dysfunction in schizophrenia and the potential for cannabis to induce psychosis has been extensively reviewed elsewhere (Arnold et al, 2012; Bossong and Niesink, 2010; Chadwick et al, 2013; Gage et al, 2016; Radhakrishnan et al, 2014; Saito et al, 2013; Semple et al, 2005; Smit et al, 2004; Volk and Lewis, 2016). In this section, we review recent preclinical work showing that CB 1 receptor transmission in the PFC and vHIPP is capable of functionally controlling mesolimbic dopaminergic activity states in the context of regulating emotional processing and memory formation.…”

Links between central CB1-receptor availability and peripheral endocannabinoids in patients with first episode psychosis

“…Furthermore, changes in blood endocannabinoid levels are associated with improvement in symptoms of psychosis 39 , which could imply that endocannabinoid signaling may not only be dysregulated in the central nervous system of psychotic patients, but also in the periphery 12 . There is an association between cannabis use and disturbances of the central ECS, providing further evidence for potential cross-talk between the endogenous peripheral and central ECSs 40,41 . However, to our knowledge, there are no data investigating the link between peripheral endocannabinoid levels and brain CB1R availability in healthy individuals or in psychosis.…”

“…CT scans were acquired prior to each PET scan for correction of attenuation and scatter. Continuous arterial blood sampling took place for the first 15 minutes of the scan which was followed by discrete blood sampling at 2,5,10,15,20,25,35,40,50,60,70,80 and 90 minutes after radioligand injection.…”