Glioma-Induced Alterations in Excitatory Neurons are Reversed by mTOR Inhibition

Area of Science:

• Neuroscience
• Oncology
• Molecular Biology

Background:

• Gliomas are aggressive brain tumors with poor prognosis, involving complex interactions with neurons in the tumor microenvironment.
• Neurons contribute to glioma symptoms and progression, and mTOR signaling influences neuronal excitability within this microenvironment.
• The precise cellular effects of mTOR inhibition on glioma-associated neuronal alterations remain unclear.

Approach:

• Utilized neuron-specific RiboTag profiling to analyze ribosome-bound mRNA in tumor-associated neurons.
• Performed morphometric analysis of dendritic spines and in vivo calcium imaging to assess neuronal structure and activity.
• Investigated the impact of glioma burden and pharmacological mTOR inhibition (AZD8055) on these neuronal parameters.

Key Points:

• Glioma burden caused downregulation of postsynaptic protein transcripts and dendritic spine density, alongside upregulation of cytoskeletal proteins.
• In vivo calcium imaging revealed progressive alterations in neuronal activity throughout tumor growth, particularly in neurons with high tumor burden.
• A single dose of an mTOR inhibitor (AZD8055) reversed glioma-induced changes in neuronal transcripts, dendritic spine density, and stimulus-evoked activity.

Conclusions:

• Glioma induces pathological neuronal plasticity, affecting mRNA, dendritic spines, and activity, driven by mTOR signaling.
• These tumor-associated neuronal changes are localized and reversible with mTOR inhibition.
• Findings support targeting neuronal signaling via mTOR inhibition as a potential therapeutic strategy for gliomas.