GABAergic Influences on Medulloblastoma

Abstract

Medulloblastoma (MB) is the most common malignant brain tumor in children and typically arises in the cerebellum, likely due to disruptions in neuronal precursor development. The primary inhibitory neurotransmitter in the central nervous system (CNS), γ-aminobutyric acid (GABA), exerts its effects through GABA_A, GABA_B, and GABA_C receptors. GABA receptor activity regulates the development and function of cerebellar neurons, including glutamatergic cerebellar granule cells (CGCs). Beyond the nervous system, GABA is also a common metabolite in non-neuronal cell types. An increasing body of evidence indicates that GABA can influence cell proliferation, differentiation, and migration in several types of adult solid tumors, including brain cancers. GABA and GABA_A receptor agonists can impair the viability and survival of MB cells, primarily acting on GABA_A receptors containing the α5 subunit. A marked expression of the gene encoding the α5 subunit is found across all MB tumor molecular subgroups, particularly Group 3 MB, which has a poor prognosis. Importantly, high levels of the γ-aminobutyric acid type A receptor subunit α5 (GABRA5) gene are associated with shorter patient overall survival in Group 3 and Group 4 MB. In contrast, high γ-aminobutyric acid type A receptor subunit β1 (GABRB1) gene expression is related to longer survival in all MB subgroups. The GABAergic system may, therefore, regulate MB cell function and tumor progression and influence patient prognosis, and is worthy of further investigation as a biomarker and therapeutic target in MB.

Keywords: GABAA receptor; GABAA α5 subunit; GABRA5; medulloblastoma; pediatric brain cancer; γ-aminobutyric acid.

Figure 1

Schematic illustration of a typical subunit composition of a functional GABA_A receptor in the CNS. The receptor is a hetero-pentameric GABA-gated Cl⁻ channel composed of a combination of five subunits.

Figure 2

Chromosome locations and cluster organization of genes encoding GABA_A receptor subunits. Transcriptional orientation is indicated by arrows. Adapted from [48].

Figure 3

GABRA5 gene expression in human MB. Data were obtained from the transcriptome dataset comprising 763 tumor samples from patients with MB as previously described by Cavalli et al. (GEO: GSE85218) [22] and analyzed with the R2 Genomics Analysis and Visualization Platform (http://r2.amc.nl). Results are presented in boxplot format as log2-transformed signal intensity. Bars show data for different (A) subgroups and (B) subtypes of MB; *** p < 0.001 compared with other groups, as indicated in the graphs.

Figure 4

GABRA5 expression and overall survival in patients with MB. Data were obtained from the transcriptome dataset comprising 763 tumor samples from patients with MB as previously described by Cavalli et al. (GEO: GSE85218) [22]. Data for different molecular subgroups of MB combined or analyzed separately are shown. Patient overall survival was measured from the day of diagnosis until death or date of last follow-up, and calculated using the Kaplan–Meier estimate, with median values and logrank statistics; p-values indicated in the panels show significant associations between gene expression and survival in Group 3 and Group 4, but not SHH and WNT MB.