16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro

Sundberg M, Pinson H, Smith RS, Winden KD, Venugopal P, Tai DJC, Gusella JF, Talkowski ME, Walsh CA, Tegmark M and Sahin M. 

Nature Communications, 2021

Bioelectronic assays help scientists uncover underlying mechanisms and a potential therapeutic target for neuropsychiatric and neurodevelopmental disorders associated with 16p11.2 deletion

Research has shown that reciprocal copy number variations of 16p11.2 are linked to neurodevelopmental disorders including autism spectrum disorder and attention deficit hyperactivity disorder and neuropsychiatric disorders such as schizophrenia, but this relationship is not fully understood. In this study, researchers used CRISPR-Cas9-edited human induced pluripotent stem cells (iPSCs) with 16p11.2 deletion (16pdel) and duplication (16pdup) differentiated into dopaminergic neurons to characterize cell-type-specific phenotypes and explore potential therapeutic compounds.

To assess spontaneous neural network activity and examine the effects of the Ras homolog family member A (RHOA)-inhibitor Rhosin on neurons, the researchers used Axion’s Maestro multielectrode array (MEA) platform. The resulting data demonstrated hyperactivity in the 16pdel iPSC-derived dopaminergic neurons, with increased spiking and bursting compared to controls, and showed that Rhosin treatment rescues the hyperactivation of the neural network. These results, along with other findings from the scientists’ multiplatform approach, demonstrate that the RHOA pathway plays an important role in the development of network hyperactivity observed in human dopaminergic neurons with 16p11.2 deletion and suggests that targeting the pathway may be a promising therapeutic approach.

To assess spontaneous neural network activity and examine the effects of the Ras homolog family member A (RHOA)-inhibitor Rhosin on neurons, the researchers used Axion’s Maestro multielectrode array (MEA) platform. The resulting data demonstrated hyperactivity in the 16pdel iPSC-derived dopaminergic neurons, with increased spiking and bursting compared to controls, and showed that Rhosin treatment rescues the hyperactivation of the neural network. These results, along with other findings from the scientists’ multiplatform approach, demonstrate that the RHOA pathway plays an important role in the development of network hyperactivity observed in human dopaminergic neurons with 16p11.2 deletion and suggests that targeting the pathway may be a promising therapeutic approach.