During these first 30 months of the project, we have developed / improved the techniques and performed the first experiments in order to unravel the role of the IDH mutated gliomas oncometabolite D2HG on glutamatergic signaling and glioma growth & epileptogenicity.
Cortical activities during human glioma surgery have been recorded in awake conditions in order to characterize the tumor vs infiltrated peritumoral vs remote healthy areas, by correlating electrophysiological activity patterns to tumor cell infiltration and MRI data (paper in preparation). The spatio-temporal pattern of epileptic activities in human postoperative peritumoral cortical tissues have been characterized and we developed software tools to better identify specific activity types (including high frequency oscillations), map them and explore their dynamics (paper in preparation). Currently, we are preparing the first trial of conductive polymer PEDOT:PSS coated microelectrodes (electrode development, electronics, reglementary preparation) during neurosurgeries.
The effects of oncometabolite D2HG on various types of AMPA, NMDA and GABAA receptors have been investigated in order to better understand its role in neuronal activities remodeling and glioma growth in vivo. In vitro studies using xenopus oocytes have been completed and we started to characterize D2HG effects on human neurons synaptic signaling ex vivo. The protocol for organotypic human postoperative cortex culture preparation has been improved. We achieved a significant percentage of cultures maintaining activity for over one week which allows us to perform co-cultures of both glioma and cortical tissues. Moreover, we have created a new in vivo rodent model of glioblastoma in which human cell lines, characterized by variable invasivity features, are grafted in the brain of an immunodeficient mouse. IDH mutation was introduced in the cell lines to study its effects. In order to explore the specific effects of D2HG (one of the multiple consequences of IDH mutation) a cannula is inserted into the brain to deliver relevant concentrations of D2HG via an implanted miniature osmotic pump. Finally, we have collaborated on the work exploring the effects of antiseizure medications on glioblastoma prognosis (in line with our fundamental research) (Pallud et al. Neurology 2022).
