GABA(A) receptors composed of the gamma2 and delta subunits have distinct properties, functions and subcellular localization, and pathological conditions differentially modulate their surface expression. Recent studies demonstrate that acute seizure activity accelerated trafficking of the gamma2 and beta2/3 subunits but not that of the delta subunit. The trafficking of the gamma2 and beta2/3 subunits is relatively well understood but that of the delta subunit has not been studied. We compared intracellular accumulation of the delta and gamma2 subunits in cultured hippocampal neurons using an antibody feeding technique. Intracellular accumulation of the delta subunit peaked between 3 and 6 h, whereas, maximum internalization of the gamma2 subunit took 30 min. In the organotypic hippocampal slice cultures internalization of the delta subunit studied using a biotinylation assay revealed highest accumulation between 3 and 5 h and that of the gamma2 subunit between 15 and 45 min. The surface half-life of the delta subunit was 171 min in cultured hippocampal neurons and 102 min in the organotypic hippocampal slice cultures. In the subsequent studies, internalization of the delta subunit was found to be dependent on network activity but independent of ligand-binding. Brain-derived neurotrophic factor (BDNF) reduced buildup of the delta subunit in the cytoplasmic compartments and increased its surface expression, and this BDNF effect was independent of network activity. BDNF effect was mediated by activation of TrkB receptors, PLCgamma and PKC. Increase in the basal PKC activity augmented cell surface stability of the delta subunit. These results suggest that rate of intracellular accumulation of the delta subunit was distinct and modulated by BDNF.