Endocannabinoid System Unlocks the Puzzle of Autism Treatment via Microglia

Abstract

Autism spectrum disorder (ASD) is a serious neurodevelopmental disorder and characterized by early childhood-onset impairments in social interaction and communication, restricted and repetitive patterns of behavior or interests. So far there is no effective treatment for ASD, and the pathogenesis of ASD remains unclear. Genetic and epigenetic factors have been considered to be the main cause of ASD. It is known that endocannabinoid and its receptors are widely distributed in the central nervous system, and provide a positive and irreversible change toward a more physiological neurodevelopment. Recently, the endocannabinoid system (ECS) has been found to participate in the regulation of social reward behavior, which has attracted considerable attention from neuroscientists and neurologists. Both animal models and clinical studies have shown that the ECS is a potential target for the treatment of autism, but the mechanism is still unknown. In the brain, microglia express a complete ECS signaling system. Studies also have shown that modulating ECS signaling can regulate the functions of microglia. By comprehensively reviewing previous studies and combining with our recent work, this review addresses the effects of targeting ECS on microglia, and how this can contribute to maintain the positivity of the central nervous system, and thus improve the symptoms of autism. This will provide insights for revealing the mechanism and developing new treatment strategies for autism.

Lipid-Based Molecules on Signaling Pathways in Autism Spectrum Disorder

“…Apart from these, the endocannabinoid system (ECS) may be involved in ASD pathophysiology [ 12 ]. The ECS is a complex network of lipid signaling pathways consisting of AA, 2-arachidonoylglycerol-derived compounds, and their G protein-coupled receptors (cannabinoid receptors CB1 and CB2) [ 13 ] Moreover, ECS is a lipid cell signaling system involved in the physiology and homeostasis of the brain.…”

“…The microglia harbor a completely functional ECS signaling system [ 12 ]. In addition, the ECS is closely involved in regulating microglia polarization [ 12 ].…”

“…The microglia harbor a completely functional ECS signaling system [ 12 ]. In addition, the ECS is closely involved in regulating microglia polarization [ 12 ]. Hence, the ECS may affect inflammation due to its role in regulating microglia.…”

“…Hence, the ECS may affect inflammation due to its role in regulating microglia. The activation of CB2 receptors not only affects the migration, proliferation, and release of proinflammatory cytokines from microglia but also promotes the transformation of microglial cells to the anti-inflammatory phenotype [ 12 ].…”

“…With respect to the role of CB1 and CB2, CBG binds CB1 and CB2 but functions as a competitive antagonist for CB1. CB1 is important for neuronal differentiation, normal axon migration, and the establishment of neuronal connectivity [ 12 ]. Early exposure of lipopolysaccharide (LPS) in rats impairs communication and cognition due to decreased ozendocannabinoid (eCB)–CB1 binding, elevated major endocannabinoid ananadamide (AEA) levels, and increased fatty acid amide hydrolase (FAAH) in the amygdala [ 12 ].…”