GABAergic neuron-to-glioma synapses in diffuse midline gliomas

Area of Science:

• Neuroscience
• Oncology
• Molecular Biology

Background:

• High-grade gliomas (HGGs) are aggressive brain tumors with distinct subtypes, including diffuse midline gliomas (DMGs).
• Neuronal activity, particularly through neuron-to-glioma synapses, is known to drive glioma progression.
• While glutamatergic synapses are studied, other neurotransmitter-mediated synapses in gliomas remain less understood.

Purpose of the Study:

• To investigate the role of non-glutamatergic neuron-to-glioma synapses in HGG progression.
• To identify the specific neurotransmitter and receptor involved in tumor-promoting synaptic communication in DMGs.
• To evaluate the therapeutic potential of targeting these newly identified synaptic pathways.

Main Methods:

• Whole-cell patch-clamp electrophysiology to record synaptic currents.
• In vivo optogenetics to manipulate neuronal activity.
• Patient-derived orthotopic xenograft models in mice to study tumor growth and response to treatment.

Main Results:

• Functional, tumor-promoting GABAergic neuron-to-glioma synapses mediated by GABA_A receptors were identified in DMGs.
• GABAergic input depolarizes DMG cells, increasing proliferation and tumor growth in vivo.
• The benzodiazepine lorazepam enhanced GABAergic signaling, accelerated DMG growth, and reduced survival in xenograft models.
• Hemispheric HGGs showed minimal depolarizing GABAergic currents, and lorazepam did not affect their growth.

Conclusions:

• GABAergic synaptic communication between neurons and H3K27M-altered DMG cells promotes tumor growth.
• This represents a novel, subtype-specific mechanism of brain cancer neurophysiology.
• Targeting GABAergic signaling may offer a therapeutic strategy for specific HGG subtypes.