Satellite Glial Cells Synthesize and Release GABA to Activate Extrasynaptic GABA_A Receptors That Modulate Dorsal Root...

Sensory neurons express extrasynaptic GABA_A receptors in their soma and axon, tonically activated by ambient GABA, modulating their excitability. However, the specific glial or neuronal origin of endogenous GABA that modulates this excitability has yet to be identified. We investigated the expression and function of enzymes involved in GABA synthesis via the ornithine-putrescine and glutamic acid pathways, and the effects of inhibiting these enzymes on the compound action potential (cAP) of primary afferent fibers. PCR analysis revealed that the dorsal root ganglia (DRG) express transcripts for ornithine decarboxylase (ODC), monoamine oxidase B (MAOB), diamine oxidase (DAO), and GAD65/67. Immunofluorescence assays confirmed the expression of ODC, MAOB, DAO, and GAT-3 proteins, as well as GABA in satellite glial cells (SGC). In contrast, neurons express DAO and ODC. However, despite the presence of GAD65 and GAD67 mRNAs, their corresponding proteins were not detected. Inhibition of ODC and MAOB, but not DAO or GAD, prevented the accumulation of GABA induced by the GABA transaminase (GABA-T) inhibitor aminooxy acetic acid in SGC cultures. Additionally, the Best1 channel blocker CaCCinh suppressed the K⁺-induced release of [³H]GABA in DRG and SGC cultures. Blocking GABA_A receptors with picrotoxin, inhibiting MAOB, and blocking Best1 all increased cAP. However, allylglycine, a GAD inhibitor, failed to elicit this effect. Likewise, the use of selegiline and CaCCinh on cAP occluded the effects of picrotoxin. These results support that GABA synthesized and released by satellite glial cells activates extrasynaptic GABA_A receptors, thereby modulating the excitability of sensory neurons.