GABA receptor activation alters astrocyte phenotype changes induced by trimethyltin via ERK signaling in the dentate gyrus of mice.

AIMS

We examined the effect of γ-aminobutyric acid (GABA) receptor activation on astrocyte phenotype changes induced by trimethyltin (TMT) in the dentate gyrus of mice.

MAIN METHODS

Male C57BL/6N mice received TMT (2.6 mg/kg, i.p.), and the expression of GABA receptors was evaluated in the hippocampus. The GABA receptor agonist baclofen (2.5, 5, or 10 mg/kg, i.p. × 5 at 12-h intervals) was administered 3-5 days after TMT treatment, and the expression of Iba-1, GFAP, and astrocyte phenotype markers was evaluated 6 days after TMT. SL327 (30 mg/kg, i.p.), an extracellular signal-related kinase (ERK) inhibitor, was administered 1 h after each baclofen treatment.

KEY FINDINGS

TMT insult significantly induced the astroglial expression of GABA receptors in the dentate molecular layer. Baclofen significantly promoted the expression of S100A10, EMP1, and CD109, but not that of C3, GGTA1, and MX1 induced by TMT. In addition, baclofen significantly increased the TMT-induced expression of p-ERK in the dentate molecular layer. Interestingly, p-ERK was more colocalized with S100A10 than with C3 after TMT insult, and a significant positive correlation was found between the expression of p-ERK and S100A10. Consistently, SL327 reversed the effect of baclofen on astrocyte phenotype changes. Baclofen also enhanced the TMT-induced astroglial expression of glial cell-derived neurotrophic factor (GDNF), an anti-inflammatory astrocytes-to-microglia mediator, and consequently attenuated Iba-1 expression and delayed apoptotic neuronal death.

SIGNIFICANCE

Our results suggest that GABA receptor activation increases S100A10-positive anti-inflammatory astrocytes and astroglial GDNF expression via ERK signaling after TMT excitotoxicity in the dentate molecular layer of mice.