GABAergic stimulation switches from enhancing to repressing BDNF expression in rat hippocampal neurons during maturation in vitro Available to Purchase

γ-aminobutyric acid (GABA) is the major inhibitory neu-rotransmitter in the adult mammalian central nervous system. However, GABA depolarizes immature rat hip-pocampal neurons and increases intracellular Ca²⁺ ([Ca²⁺]_i). Here we show, that GABA and the GABA_A receptor agonist muscimol induce c-Fos immunoreactivity and increase BDNF mRNA expression in embryonic hip-pocampal neurons cultured for 5 days. In contrast, after 3 weeks in culture, GABA and muscimol failed to induce c-fos and BDNF expression. Fura-2 fluorescence microscopy revealed that muscimol produces a dihydropyridine-sensitive transient increase in [Ca²⁺]_i, comparable to the effect of the non-NMDA receptor agonist kainic acid in neurons cultured for 5 days, but not in 3-week-old cultures. The increase in c-Fos immunoreactivity and BDNF mRNA levels by GABA were dependent upon the activation of voltage-gated Ca²⁺ channels, as shown using the L-type specific Ca²⁺ channel blocker nifedipine. The differential regulation of c-fos and BDNF expression by GABA and muscimol in developing and mature hippocampal neurons is due to a switch in the ability of GABA_A receptors to activate voltage-gated Ca²⁺ channels. These observations support the hypothesis that GABA might have neurotrophic effects on embryonic or perinatal hippocampal neurons, which are mediated by BDNF.