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Glioma-induced alterations in excitatory neurons are reversed by mTOR inhibition
Alexander R Goldberg1, Athanassios Dovas1, Daniela Torres1
1Department of Pathology and Cell Biology, Irving Cancer Research Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
Abstract:
Gliomas are aggressive neoplasms that diffusely infiltrate the brain and cause neurological symptoms, including cognitive deficits and seizures. Increased mTOR signaling has been implicated in glioma-induced neuronal hyperexcitability, but the molecular and functional consequences have not been identified. Here, we show three types of changes in tumor-associated neurons: (1) downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development and upregulation of cytoskeletal transcripts via neuron-specific profiling of ribosome-bound mRNA, (2) marked decreases in dendritic spine density via light and electron microscopy, and (3) progressive functional alterations leading to neuronal hyperexcitability via in vivo calcium imaging. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed these tumor-induced changes. These findings reveal mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma and suggest new strategies for treating glioma-associated neurological symptoms.
Insights
Glioma tumors alter neuron function and structure by increasing mTOR signaling. A targeted drug reversed these harmful changes, offering new hope for treating neurological symptoms associated with brain tumors.
Area of Science:
- Neuroscience
- Oncology
- Molecular Biology
Background:
- Gliomas are aggressive brain tumors causing neurological deficits.
- Increased mechanistic target of rapamycin (mTOR) signaling is linked to glioma-induced neuronal hyperexcitability.
- The precise molecular and functional impacts of mTOR signaling on tumor-associated neurons remain unclear.
Purpose of the Study:
- To investigate the molecular and functional consequences of increased mTOR signaling in neurons near gliomas.
- To identify pathological changes in tumor-associated neurons.
- To evaluate the therapeutic potential of mTOR inhibition in reversing these changes.
Main Methods:
- Neuron-specific profiling of ribosome-bound mRNA to analyze transcriptomic changes.
- Light and electron microscopy to assess dendritic spine density.
- In vivo calcium imaging to evaluate neuronal function.
- Pharmacological intervention using AZD8055, a combined mTORC1/2 inhibitor.
Main Results:
- Tumor-associated neurons exhibited downregulated transcripts for synaptic proteins and dendritic spine development, alongside upregulated cytoskeletal transcripts.
- A significant decrease in dendritic spine density was observed in these neurons.
- Progressive functional alterations leading to neuronal hyperexcitability were detected.
- A single dose of AZD8055 effectively reversed these tumor-induced molecular, structural, and functional deficits.
Conclusions:
- Glioma promotes mTOR-driven pathological plasticity in adjacent neurons.
- These findings highlight novel therapeutic strategies targeting mTOR to alleviate neurological symptoms in glioma patients.
- Understanding these mechanisms can lead to improved treatments for brain tumor-associated neurological complications.
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