Endocannabinoids (eCB) are key regulators of excitatory/inhibitory neurotransmission at cannabinoid-1-receptor (CB1R)-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 CB1R desensitization. We employed the MAGL knock-out mouse (MAGL-/-), a genetic model of congenital and sustained elevation of 2-AG levels in the brain, to provide morphological and biochemical evidence for β-arrestin2-mediated CB1R 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 CB1R/β-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 CB1R-positive excitatory terminals in the mPFC, or vesicular GABA transporter (VGAT) at CB1R-positive inhibitory terminals in the amygdala and hippocampus. The impairment of CB1R signaling in MAGL-/- 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 β-arrestin2-mediated desensitization of CB1R in MAGL-/- mice, with impact on the synaptic plasticity of brain circuits involved in emotional functions.

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

Imperatore R.;
2015-01-01

Abstract

Endocannabinoids (eCB) are key regulators of excitatory/inhibitory neurotransmission at cannabinoid-1-receptor (CB1R)-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 CB1R desensitization. We employed the MAGL knock-out mouse (MAGL-/-), a genetic model of congenital and sustained elevation of 2-AG levels in the brain, to provide morphological and biochemical evidence for β-arrestin2-mediated CB1R 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 CB1R/β-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 CB1R-positive excitatory terminals in the mPFC, or vesicular GABA transporter (VGAT) at CB1R-positive inhibitory terminals in the amygdala and hippocampus. The impairment of CB1R signaling in MAGL-/- 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 β-arrestin2-mediated desensitization of CB1R in MAGL-/- mice, with impact on the synaptic plasticity of brain circuits involved in emotional functions.
2015
2-arachidonoylglycerol (2-AG); anxiety-like behavior; CB; 1; R; endocannabinoids; MAGL-KO mice; synaptic plasticity; Action Potentials; Animals; Anxiety; Arachidonic Acids; Arrestins; Brain; Disease Models, Animal; Endocannabinoids; Exploratory Behavior; Gene Expression Regulation; Glutamic Acid; Glycerides; Hindlimb Suspension; Immunoprecipitation; Lipid Metabolism; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microdialysis; Monoacylglycerol Lipases; Receptor, Cannabinoid, CB1; Vesicular Glutamate Transport Protein 1; beta-Arrestins
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12070/42857
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