Inhibitory circuit dysfunction as a potential contributor to cortical reorganization in Glioblastoma progression

Glioblastoma (GBM) is a highly aggressive brain tumor that infiltrates surrounding brain tissue, profoundly affecting adjacent cortical areas. This study investigates how GBM reshapes the peritumoral cortex by examining plasticity changes in two GBM mouse models. Using optogenetic stimulation, we observed altered motor mapping and reduced cortical specificity in GBM mice compared to controls. Morphologically, GBM mice showed a reduction in dendritic spines, perineuronal nets, and inhibitory markers. Functionally, inhibitory circuits were markedly impaired, characterized by an increased frequency of spontaneous inhibitory currents and a decrease in their amplitude. Our findings highlight the critical role of inhibitory circuit disruption in driving cortical reorganization and loss of motor map specificity. The reduction of parvalbumin and somatostatin interneurons, degradation of perineuronal nets, and imbalance in the excitation/inhibition ratio contribute to maladaptive plasticity, increasing the risk of hyperexcitability and seizures. These insights offer a basis for developing therapeutic strategies aimed at restoring inhibitory function, mitigating GBM-induced cortical changes, and potentially improving patient outcomes.