# Single-nucleus RNA sequencing: immature excitatory neurons and transformed glia build human BRAFV600E-negative gangliogliomas

## TL;DR

This study explores BRAFV600E-negative gangliogliomas, revealing immature excitatory neurons and transformed glia that may contribute to epilepsy.

## Contribution

The study identifies unique molecular and cellular profiles in BRAFV600E-negative gangliogliomas using single-nucleus RNA sequencing.

## Key findings

- BRAFV600E-negative gangliogliomas show immature excitatory neurons with enhanced glutamatergic signaling.
- Metabolically active astrocytes and oligodendrocytes are present in these tumors, potentially contributing to epileptogenicity.

## Abstract

Gangliogliomas are glioneuronal neoplasms, generally with a benign evolution, accounting for the most common tumours in patients with long-term pharmacoresistant epilepsy. BRAFV600E has been detected in a high percentage of World Health Organization grade 1 gangliogliomas. However, biopsy collections from epilepsy patients include tumours that meet neuropathological ganglioglioma criteria but lack the BRAFV600E mutation. The molecular pathology of such BRAFV600E-negative gangliogliomas remains largely unexplored. We here focused on decoding the molecular and cellular profiles of these BRAFV600E-negative gangliogliomas at the single-cell resolution. Our results identify an exclusive profile in excitatory, but not inhibitory, neurons, astrocytes and oligodendrocytes in BRAFV600E-negative gangliogliomas. Moreover, we confirm the presence of immature excitatory neurons with higher expression of genes related to glutamatergic transmission as well as metabolically active astro- and oligodendrocytes which may contribute to epileptogenicity. Our study provides important resources to understand the molecular profile of BRAFV600E-negative gangliogliomas aiming to drive forward future research directions to novel and tailored treatment options for epilepsy.

Cases-Cunillera et al. report that BRAFV600E-negative gangliogliomas display immature excitatory neurons with enhanced glutamatergic signaling and metabolically altered glial populations. These findings uncover distinct transcriptional signatures underlying epileptogenicity and highlight potential therapeutic targets beyond the Mitogen-Activated Protein Kinase (MAPK) pathway.

Graphical Abstract