The influence of the raphe nucleus and serotonin on progression and neurocognition of diffuse intrinsic pons glioma

• Applicant: Dr. Richard Drexler
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases ; Clinical Neurology; Neurosurgery and Neuroradiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539349120

We seek to characterize effects of serotonergic neurons in general and serotonin specifically on DIPG pathobiology. Serotonin is the most widely distributed “neuromodulator” neurotransmitter in the brain and modulates a broad range of physiological and behavioral functions in health and disease. All serotonergic neurons are located in brainstem nuclei and projection broadly throughout the brain. Here, the raphe nucleus – located in the midline of the brainstem, where DIPG originates - is of particular importance as it contains 35% of ~26,0000 serotonin-producing neurons in the mouse brain and recent studies have defined clusters with specific functions within the raphe nucleus. DIPG is not only influenced by neurons, but also reciprocally influences neuronal function. Given the role of serotonergic neurons in epileptic seizures, anxiety, and depression, the potential influence of serotonergic neuron-tumor interactions on tumor-associated depression, anxiety and neurocognition in children suffering from DIPG is also of great interest. My research will hopefully elucidate how the serotonergic system is involved in tumor progression and neurophysiological decline in children suffering from DIPG. In preliminary studies, we have found that human DIPG cells express serotonin receptor subunit genes, and that serotonin promotes DIPG cell proliferation in vitro. We will now combine our patient-derived and genetically engineered DIPG animal models and tissue cultures with recently developed tools to study the serotonin system in vivo. Using optogenetic stimulation of serotonergic neuronal activity in mice bearing patient-derived orthotopic DIPG xenografts or murine DIPG allografts in the brainstem and in the cerebral cortex, to which DIPG frequenctly spreads, we will determine the influence of serotonergic neuronal activity on DIPG progression, assessing tumor cell proliferation, invasion, tumor burden and mouse survival. We will ascertain exactly which subregions of the raphe nucleus (e.g., dorsal raphe nucleus) may have a predominant role in promoting tumor growth. Reciprocally, we will determine which components of serotonergic circuitry may be influenced by the tumor. In addition, we will investigate which serotonergic neurons projection to tumor cells and identify possible co-expression of neurotransmitters such as glutamate. We will assess the possibility of serotonergic neuron-to-glioma synapses in DIPG using electron microscopy and patch clamp electrophysiology, as the Monje lab has done extensively in the past to discover glutamatergic and GABAergic neuron-to-glioma synapses in DIPG. After unraveling the role of the serotonergic system and its underlying mechanisms in DIPG, we will test serontonin antagonists as potential therapeutics for DIPG.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Michelle Monje-Deisseroth, Ph.D.