Serotonergic neuron-glioma interactions drive high-grade glioma pathophysiology

Abstract High-grade gliomas are lethal brain cancers that are powerfully regulated by glutamatergic neurons through activity-dependent paracrine factors and functional neuron-to-glioma synapses. Here, we report that serotonergic neurons promote the proliferation of high-grade gliomas throughout the brain. Serotonergic neuronal activity drives circuit-specific increases in high-grade glioma proliferation, calcium transients, and reduced survival. This growth-promoting effect is chiefly mediated by activation of the serotonin (5-hydroxytryptamine; 5HT) receptor 5HT2A on glioma cells. Knock out or pharmacological blockade of 5HT2A receptors in glioma abrogated the glioma growth-promoting effects of serotonergic neuronal activity, while serotonergic psychedelic drugs robustly promote malignant cell proliferation. Gliomas alter serotonergic neuronal activity patterns, resulting in elevated serotonin release into the tumor microenvironment. Together, these findings uncover pathogenic, feed-forward interactions between serotonergic neurons and glioma cells. Competing Interest Statement MM and KD hold equity in Maplight Therapeutics and Stellaromics. K.D. is a founder and consultant for MapLight Therapeutics and Stellaromics. K.D. is a consultant for Modulight.bio and RedTree. Stanford University is filing patent applications on targeting ICAM, NCAM and 5HT2A in gliomas, with MM and RD as inventors.