CNSC-10. GLIOBLASTOMA CELLS IMITATE NEURON’S EXCITABILITY IN ACUTE AND ORGANOTYPIC HUMAN BRAIN SLICES

Abstract

Abstract Glioblastoma (GBM) is a highly lethal cancer due to its inter- and intra-patient molecular and physiological heterogeneity, and its complex interaction with brain tissue. Recent findings demonstrate that Neuron-to-brain tumor-synaptic-communications (NBTSCs) engage in a vicious cycle of enhanced neuronal activity, driving glioma progression and invasion and tumor-induced epilepsy. However, the physiology of these synaptic interactions in the tumor-infiltrated human neocortex remains largely uncharacterized. To address this gap, our study focused on investigating the intrinsic electrical properties of glioma cells and NBTSCs in the tumor-infiltrated human cortex using a unique experimental workflow involving acute and cultured human tumor-infiltrated brain slices. Via an adeno-associated virus-assisted gene delivery technique, we selectively express fluorescence proteins in a cell-type specific manner. By performing fluorescence-guided whole-cell patch clamp recording, we characterized the electrophysiological properties of glioma cells and neurons under the tumor microenvironment. We observed that glioma cells from tumor-infiltrated human brain samples displayed depolarized resting membrane potential (-32.21 ± 2.1mV) and high input resistance (1.24 ± 0.18 GΩ). Approximately 69.2% of glioma cells exhibited spikelets or distorted-action potentials upon current injection. Consistent with other studies, a subset of glioma cells (11.8%) exhibited spontaneous excitatory postsynaptic currents (sEPSC). In addition, the tumor-infiltrated microenvironment significantly influences the proximal neurons’ physiology and the neuronal microcircuitry, leading to abnormal intrinsic electrical properties, depolarized resting membrane potential (-37.66 ± 4.32 mV), and a significant reduction in spontaneous synaptic input frequency. Collectively, our study consolidates the existence of NBTSCs in human cancer patients and reveals that glioma cells exhibit neuron-like excitability, which is contrary to the common understanding that they are considered as non-excitable. Under the tumor microenvironment, neurons display hyperexcitability. Our newly established organotypic human brain slice culture platform provides potential grounds for exploring further the biological characteristics of gliomas and NBTSCs.