Ketamine impairs growth cone and synaptogenesis in human GABAergic projection neurons via GSK-3β and HDAC6 signaling

The growth cone guides the axon or dendrite of striatal GABAergic projection neurons that protrude into the midbrain and cortex and form complex neuronal circuits and synaptic networks in a developing brain, aberrant projections and synaptic connections in the striatum related to multiple brain disorders. Previously, we showed that ketamine, an anesthetic, reduced dendritic growth, dendritic branches, and spine density in human striatal GABAergic neurons. However, whether ketamine affects the growth cone, the synaptic connection of growing striatal GABAergic neurons has not been tested. Using human GABAergic projection neurons derived from human inducible pluripotent stem cells (hiPSCs) and embryonic stem cells (ES) in vitro, we tested ketamine effects on the growth cones and synapses in developing GABAergic neurons by assessing the morphometry and the glycogen synthase kinase-3 (GSK-3) and histone deacetylase 6 (HDAC6) pathway. Ketamine exposure impairs growth cone formation, synaptogenesis, dendritic development, and maturation via ketamine-mediated activation of GSK-3 pathways and inhibiting HDAC6, an essential stabilizing protein for dendritic morphogenesis and synapse maturation. Our findings identified a novel ketamine neurotoxic pathway that depends on GSK-3 beta and HDAC6 signaling, suggesting that microtubule acetylation is a potential target for reducing ketamine's toxic effect on GABAergic projection neuronal development.

Automated summary

This study revealed the mechanisms by which ketamine affects the growth cones and synapse formation of developing GABAergic neurons using human pluripotent stem cells. The results indicate that ketamine impairs growth cone formation, synaptogenesis, and dendrite maturation through the activation of GSK-3β pathway and inhibition of HDAC6.