Pharmacological inhibition of the primary endocannabinoid producing enzyme, DGL‐α, induces autism spectrum disorder‐like and co‐morbid phenotypes in adult C57BL/J mice

Abstract

Accumulating evidence links dysfunction in the endocannabinoid system (ECS) with the pathology of neurodevelopmental disorders, particularly autism spectrum disorder (ASD). Variants in ECS genes CNR1 and DAGLA are associated with neurological phenotypes in humans. The endocannabinoids (eCBs), 2-AG and AEA, which act at the primary cannabinoid receptor (CB1), mediate behaviors relevant to neurodevelopmental disorders. The overlap between these eCBs is poorly understood. Most ECS studies have focused on stress responses, anxiety, and epilepsy, however, its role in social behavior and communication has only recently come under investigation. This represents a critical gap in our understanding of the ECS and its relationship to ASD. Furthermore, the increasing prevalence of ASD and a lack of therapeutics emphasize a crucial need for novel therapeutic targets. To this aim, we used an inhibitor of the eCB producing enzyme DGL-α, DO34, and the CB1 inverse agonist, rimonabant, to evaluate the role of the primary eCB, 2-AG, in ASD. Adult male C57BL/6J mice were used in a series of behavioral paradigms which assessed social behavior, social communication, repetitive behaviors, anxiety and locomotor activity. DO34 and rimonabant increased anxiety-like behavior, while only DO34 induced hyperactivity, social deficits, and repetitive self-grooming behavior. These data indicate that reduced 2-AG bioavailability, or CB1 inhibition, each induce unique respective behavioral phenotypes relevant to neurodevelopmental disorders, particularly ASD. This suggests fundamental differences in CB1 signaling via 2-AG and the CB1 receptor itself, particularly for social behaviors, and that 2-AG signaling may represent a target for the development of novel therapeutics. Lay Summary: Endocannabinoids play a critical role in the developing nervous system. Alterations in the endocannabinoid system are linked to neurodevelopmental disorders. Studies suggest these variants may play a critical role in the core symptoms of autism spectrum disorder. In this study, pharmacological inhibition of the primary endocannabinoid producing enzyme, DGL-α, induced a constellation of deficits in behavioral domains associated with autism.

Paracetamol use during pregnancy — a call for precautionary action

“…Other data suggest that the analgesic effect of APAP acts through the endocannabinoid system 159 . The endocannabinoid system is a complex network of lipid signalling pathways that have an important role in the developing nervous system 160 . Alterations of the endocannabinoid system have been found in both the brain and the immune system of humans with ASD 161 , 162 .…”

FMR1 and Autism, an Intriguing Connection Revisited

“…Importantly, pharmacological augmentation of 2-AG levels blocked these deficits in social behavior from occurring. Pharmacological inhibition of DGL-α activity at adulthood caused social impairments, a communication deficit, and repetitive behavior in C57BL6 mice [108].…”

“…Each of these defects causes increased Ca 2+ entry and neurotransmitter release (computational dysfunction). [108].…”

“…Each of these components has notable pre-clinical and clinical evidence linking them to lost FMRP function and ASD [36,65,85,90,100,[109][110][111]. Importantly, these components can be manipulated genetically and pharmacologically to induce or rescue some ASD phenotypes, which makes them attractive targets for inquiry into underlying pathology, and potential therapies [85,99,108,112,113].…”

“…Mutations in (h) the β4 regulatory unit of BKCa channels, (i) CB1, (j) Homer1a, (k) Shank3, and (l) NMDA channels have associations with syndromic and non-syndromic ASD. Each of these defects causes increased Ca 2+ entry and neurotransmitter release (computational dysfunction) [108]…”