GABA(A)-mediated toxicity of hippocampal neurons in vitro

In the present study, we examined whether the elevation of GABA by gamma-vi nyl-GABA protects cultured rat fetal hippocampal neurons against toxicity i nduced by a 20-min incubation with 100 mu M L-glutamate. Neither a 24-h pre treatment nor posttreatment with gamma-vinyl-GABA (100 mu M) had any neurop rotective effects, as determined by counting microtubule-associated protein -2 positive cells and lactate dehydrogenase assay 24 h after the glutamate treatment. Unexpectedly, gamma-vinyl-GABA alone induced a 20% loss of micro tubule-associated protein-2-positive cells in a culture that was grown in m edium containing 25 mM KCl. The toxic effect of gamma-vinyl-GABA was mimick ed by a 24-h treatment with GABA (100 mu M) and the GABA(A) receptor agonis t, muscimol (10 mu M), but not the GABA(A) receptor agonist, baclofen (10 m u M). The GABA, receptor antagonist, bicuculline (10 mu M), protected again st gamma-vinyl-GABA and GABA-evoked toxicity. Neither y-vinyl-GABA nor GABA was toxic in culture medium containing 15 mM KCl. These data indicate that , under depolarizing conditions, an increased GABA level is toxic for a sub population of developing hippocampal neurons in vitro. The effect is GABA(A ) receptor-mediated. These data provide a new view for understanding neurod egenerative processes, and raise a question of the safety of therapies aime d at increasing GABA concentration following brain insults, especially in i mmature brains.