Positive feed-back regulation between GABAA receptor signaling and Brain-derived Neurotrophic Factor (BDNF) release in developing neurons.

Abstract

During the early development of the nervous system, gamma-aminobutyric acid (GABA) type A receptor (GABAAR)-mediated signaling parallels the neurotrophin/Trk-dependent signaling in controlling a number of processes, from cell proliferation and migration, via dendritic and axonal outgrowth, to synapse formation and plasticity. Here we present the first evidence that these two signaling systems regulate each other through a complex positive feed-back mechanism. We first demonstrate that GABAAR activation leads to an increase in the cell surface expression of these receptors in cultured embryonic cerebrocortical neurons, specifically at the stage when this activity causes depolarization of the plasma membrane and Ca2+ influx through L-type voltage-gated Ca2+ channels. We further demonstrate that GABAAR activity triggers release of the brain-derived neurotrophic factor (BDNF) which, in turn, by activating tropomyosin-related kinase B (TrkB) receptors, mediates the observed increase in cell surface expression of GABAARs. This BDNF/TrkB-dependent increase in surface levels of GABAARs requires the activity of the phosphoinositide 3-kinase (PI3K) and protein kinase C (PKC), and does not involve the extracellular signal-regulated kinase (ERK) 1&2 activity. The increase in GABAARs surface levels occurs due to an inhibition of the receptor endocytosis by BDNF, while the receptor re-insertion into the plasma membrane remains unaltered. Thus, GABAAR activity is a potent regulator of the BDNF release during neuronal development, and, at the same time, it is strongly enhanced by the activity of the BDNF/TrkB/PI3K/PKC signaling pathway.