CNSC-68. LEVETIRACETAM THERAPEUTICALLY TARGETS GABAERGIC SYNAPSES IN DIFFUSE MIDLINE GLIOMA

Abstract Pediatric high-grade gliomas (HGGs) are the leading cause of brain cancer-related death in children. HGGs include distinct subtypes defined by anatomical location as well as molecular characteristics that stratify into H3K27M-altered diffuse midline gliomas (DMG) and hemispheric HGGs such as isocitrate dehydrogenase-wild type (IDH-WT) glioblastoma. Neuronal activity drives HGG progression both through paracrine signaling and direct neuron-to-glioma synapses. Using whole-cell patch clamp electrophysiology, in vivo optogenetics, and patient-derived glioma xenograft mouse models, we identify functional, tumor-promoting GABAergic neuron-to-glioma synapses mediated by GABAA receptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to chloride uptake by the Na-K-2Cl cotransporter NKCC1 and consequent elevated intracellular chloride concentration. In contrast, depolarizing GABAergic currents were not detected in IDH-WT HGG. Membrane depolarization is known to increase glioma proliferation and accordingly, we find that the activity of GABAergic interneurons promotes DMG proliferation in vivo. Increasing GABA signaling with the benzodiazepine lorazepam increases glioma proliferation and reduces survival in xenograft models of DMG but not IDH-WT HGG. Conversely, we find that the anti-seizure medication levetiracetam attenuates low-frequency depolarizing GABAergic synaptic currents in a glioma-specific manner, reducing those in DMG but not in healthy neurons. The effect in DMG is independent of action on synaptic vesicle glycoprotein 2A (SV2A), the chief mechanism by which levetiracetam suppresses seizures. Levetiracetam reduces glioma proliferation and extends survival of mice bearing DMG xenografts, but not IDH-WT HGG xenografts. Retrospective real-world clinical data demonstrate longer overall survival for children with DMG who were taking levetiracetam, which was not evident in pediatric hemispheric HGG. These findings uncover growth-promoting GABAergic synaptic communication between GABAergic neurons and DMG cells, underscoring a tumor subtype-specific mechanism of brain cancer neurophysiology with potentially important implications for commonly used drugs in this disease context, which should be further studied in future prospective clinical studies.