The Endocannabinoid System Regulates Synaptogenesis in a Cortical Spheroid Model of Fetal Neurodevelopment

Abstract

The endocannabinoid system plays a complex role in synaptogenesis and the subsequent development of neural circuitry during fetal brain development. The cannabinoid receptor type 1 controls synaptic strength at both excitatory and inhibitory synapses and thus contributes to the balance of excitatory and inhibitory signaling. Imbalances in the ratio of excitatory to inhibitory synapses have been implicated in various neuropsychiatric disorders associated with dysregulated central nervous system development including autism spectrum disorder, epilepsy, and schizophrenia. The role of the endocannabinoid system in human brain development has been difficult to study but advances in induced pluripotent stem cell technology have allowed us to model the fetal brain environment. Our cortical spheroid model resembles the cortex of the dorsal telencephalon during mid-fetal gestation and possesses functional synapses and spontaneous activity. Using SR141716A, we observed an increase in excitatory, and to a lesser extent, inhibitory synaptogenesis as measured by confocal image analysis. We also observed increased variability of neural activity and decreased GTPase RhoA activity. Overall, we have established that cortical spheroids express ECS components and are thus a useful model for exploring endocannabinoid mediation of childhood neuropsychiatric disease.