Genetic deletion of monoacylglycerol lipase leads to impaired cannabinoid receptor CB₁R signaling and anxiety‐like behavior

Abstract

Endocannabinoids (eCB) are key regulators of excitatory/ inhibitory neurotransmission at cannabinoid-1-receptor (CB 1 R)-expressing axon terminals. The most abundant eCB in the brain, that is 2-arachidonoylglycerol (2-AG), is hydrolyzed by the enzyme monoacylglycerol lipase (MAGL), whose chronic inhibition in the brain was reported to cause CB 1 R desensitization. We employed the MAGL knock-out mouse (MAGLÀ/À), a genetic model of congenital and sustained elevation of 2-AG levels in the brain, to provide morphological and biochemical evidence for b-arrestin2-mediated CB 1 R desensitization in brain regions involved in the control of emotional states, that is, the prefrontal cortex (PFC), amygdala, hippocampus and cerebellar cortex. We found a widespread CB 1 R/b-arrestin2 co-expression in the mPFC, amygdala and hippocampus accompanied by impairment of extracellular signal-regulated kinase signaling and elevation of vesicular glutamate transporter (VGluT1) at CB 1 R-positive excitatory terminals in the mPFC, or vesicular GABA transporter (VGAT) at CB 1 R-positive inhibitory terminals in the amygdala and hippocampus. The impairment of CB 1 R signaling in MAGLÀ/À mice was also accompanied by enhanced excitatory drive in the basolateral amygdala (BLA)-mPFC circuit, with subsequent elevation of glutamate release to the mPFC and anxiety-like and obsessive-compulsive behaviors, as assessed by the light/dark box and marble burying tests, respectively. Collectively, these data provide evidence for a barrestin2-mediated desensitization of CB 1 R in MAGLÀ/À mice, with impact on the synaptic plasticity of brain circuits involved in emotional functions.

Broad impact of deleting endogenous cannabinoid hydrolyzing enzymes and the CB1 cannabinoid receptor on the endogenous cannabinoid-related lipidome in eight regions of the mouse brain

“…Although a study by Imperatore and colleagues did not find any differences in AEA in the PFC, amygdala, HIPP or CER of MAGL KO, they did find that desensitization of CB 1 was brain region dependent. The desensitization of CB 1 in the HIPP and amygdala of MAGL KO was of particular importance, because it was linked to anxiety-like behavior [57]. This means that adaptations to a missing enzyme are not uniform across the brain, and elevations in 2-AG signaling have different consequences for neurotransmission and behavior depending on which neural circuitry is affected.…”

“…Indeed, the HIPP was one of the most affected areas in CB 1 KO mice. The disruption of CB 1 signaling in the HIPP is hypothesized to impair discriminative memory and is associated with anxiety-like behaviors [57]. Therefore, it appears that the STR is a more resilient brain area when it comes to maintaining homeostatic lipid metabolism after challenges to CB 1 signaling.…”

Repeated administration of phytocannabinoid Δ9-THC or synthetic cannabinoids JWH-018 and JWH-073 induces tolerance to hypothermia but not locomotor suppression in mice, and reduces CB1 receptor expression and function in a brain region-specific manner

“…Indeed, the effects of repeated Δ 9 -THC on CB1R expression and function were at least as pronounced as those of repeated exposure to the two high efficacy SCBs. Further mechanistic studies will be required to more fully understand the biochemical basis of CB1R downregulation and desensitization, but recent evidence suggests an important role for p-arrestin2 (Imperatore et al, 2015)…”

Synaptic functions of endocannabinoid signaling in health and disease

“…Genetic deletion of MAGL increased 2-AG levels in the PFC, enhanced the excitatory drive to the PFC and was associated to an anxiogenic phenotype through desensitized CB 1 signaling (Imperatore et al, 2015). Increased anxiety-like behaviors were also observed in mice fed with a diet deficient in n-3 polyunsaturated fats, which elevates 2-AG levels (Watanabe et al, 2003) and induces a desensitized or uncoupled state in presynaptic CB 1 in the PFC (Lafourcade et al, 2011).…”