AMPAR Subunit Gene Expression Marks a Synaptic Transcriptional State in Lower-Grade Glioma

Background: Glutamatergic neuron-to-glioma signaling mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) has emerged as an important mechanism in glioma progression. Objectives/Methods: We analyzed the expression of the AMPAR subunit genes GRIA1, GRIA2, GRIA3, and GRIA4 in lower-grade glioma (LGG). Results: Expression of GRIA1-GRIA4 was highest in IDH-mutant/1p19q-codeleted tumors and lowest in IDH-wildtype tumors across both The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) cohorts. High expression of each GRIA gene was associated with longer overall survival (OS). Transcriptome-wide analyses identified positive correlations between an AMPAR score and genes involved in synaptic organization, neuronal connectivity, and neurotransmission. Co-expression analyses demonstrated coordinated expression between GRIA1-GRIA4 and genes encoding AMPAR auxiliary proteins. Gene Ontology (GO) enrichment revealed overrepresentation of synaptic signaling, trans-synaptic communication, and synapse organization. Although the AMPAR score was associated with favorable survival in univariate analyses, it did not retain independent prognostic significance after adjustment for key clinicomolecular variables. Elevated expression of AMPAR subunit genes in LGG was associated with favorable molecular subtypes and a synaptic transcriptional program. Conclusions: These findings suggest that GRIA1-GRIA4 expression is associated with a synaptically enriched transcriptional program in LGG, although its cellular origin remains uncertain.