GABAergic neuron-to-glioma synapses in diffuse midline gliomas.

in Nature by Tara Barron, Belgin Yalçın, Minhui Su, Youkyeong Gloria Byun, Avishai Gavish, Kiarash Shamardani, Haojun Xu, Lijun Ni, Neeraj Soni, Vilina Mehta, Samin Maleki Jahan, Yoon Seok Kim, Kathryn R Taylor, Michael B Keough, Michael A Quezada, Anna C Geraghty, Rebecca Mancusi, Linh Thuy Vo, Enrique Herrera Castañeda, Pamelyn J Woo, Claudia K Petritsch, Hannes Vogel, Kai Kaila, Michelle Monje

TLDR

  • This study identifies functional GABAergic neuron-to-glioma synapses in high-grade gliomas, particularly in diffuse midline gliomas, which promote glioma growth and proliferation.
  • The findings suggest that targeting GABAergic signaling may be a viable therapeutic approach for treating diffuse midline gliomas, but further research is needed to explore its potential in other glioma subtypes.

Abstract

High-grade gliomas (HGGs) are the leading cause of brain cancer-related death. HGGs include clinically, anatomically and molecularly distinct subtypes that stratify into diffuse midline gliomas (DMGs), such as H3K27M-altered diffuse intrinsic pontine glioma, and hemispheric HGGs, such as IDH wild-type glioblastoma. Neuronal activity drives glioma progression through paracrine signallingand neuron-to-glioma synapses. Glutamatergic AMPA receptor-dependent synapses between neurons and glioma cells have been demonstrated in paediatricand adulthigh-grade gliomas, and early work has suggested heterogeneous glioma GABAergic responses. However, neuron-to-glioma synapses mediated by neurotransmitters other than glutamate remain understudied. Using whole-cell patch-clamp electrophysiology, in vivo optogenetics and patient-derived orthotopic xenograft models, we identified functional, tumour-promoting GABAergic neuron-to-glioma synapses mediated by GABAreceptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 chloride transporter function and consequently elevated intracellular chloride concentration in DMG malignant cells. As membrane depolarization increases glioma proliferation, we found that the activity of GABAergic interneurons promotes DMG proliferation in vivo. The benzodiazepine lorazepam enhances GABA-mediated signalling, increases glioma proliferation and growth, and shortens survival in DMG patient-derived orthotopic xenograft models. By contrast, only minimal depolarizing GABAergic currents were found in hemispheric HGGs and lorazepam did not influence the growth rate of hemispheric glioblastoma xenografts. Together, these findings uncover growth-promoting GABAergic synaptic communication between GABAergic neurons and H3K27M-altered DMG cells, underscoring a tumour subtype-specific mechanism of brain cancer neurophysiology.

Overview

  • The study investigates the role of GABAergic neuron-to-glioma synapses in high-grade gliomas (HGGs), specifically focusing on diffuse midline gliomas (DMGs) with H3K27M alterations.
  • The researchers used a combination of whole-cell patch-clamp electrophysiology, in vivo optogenetics, and patient-derived orthotopic xenograft models to examine the functional and tumor-promoting effects of GABAergic synapses in DMGs.
  • The primary objective is to understand the physiological mechanisms underlying glioma growth and to identify potential therapeutic targets for the treatment of HGGs.

Comparative Analysis & Findings

  • Functional GABAergic neuron-to-glioma synapses were identified in DMGs, which had a depolarizing effect on DMG cells due to elevated intracellular chloride concentration.
  • GABAergic input was found to promote DMG proliferation in vivo, whereas minimal depolarizing GABAergic currents were detected in hemispheric HGGs.
  • Lorazepam, a benzodiazepine that enhances GABA-mediated signaling, increased glioma proliferation and growth and shortened survival in DMG patient-derived orthotopic xenograft models.

Implications and Future Directions

  • The study highlights a tumor subtype-specific mechanism of brain cancer neurophysiology, emphasizing the importance of considering individual glioma subtypes when targeting therapeutic strategies.
  • Further research is needed to investigate the role of GABAergic synapses in other glioma subtypes and to explore the potential therapeutic applications of lorazepam or other GABA receptor modulators in treating DMGs.
  • The study's findings also underscore the need for continued investigation into the complex interplay between glioma cells and their neural microenvironment to better understand the molecular mechanisms driving glioma progression.
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