Positive Feedback Regulation between γ-Aminobutyric Acid Type A (GABAA) Receptor Signaling and Brain-derived Neurotrophic Factor (BDNF) Release in Developing Neurons

Abstract

During the early development of the nervous system, ␥-aminobutyric acid (GABA) type A receptor (GABA A R)-mediated signaling parallels the neurotrophin/tropomyosin-related kinase (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 feedback mechanism. We first demonstrate that GABA A R 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 Ca 2؉ influx through L-type voltage-gated Ca 2؉channels. We further demonstrate that GABA A R activity triggers release of the brain-derived neurotrophic factor (BDNF), which, in turn by activating TrkB receptors, mediates the observed increase in cell surface expression of GABA A Rs. This BDNF/TrkB-dependent increase in surface levels of GABA A Rs requires the activity of 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 GABA A R surface levels occurs due to an inhibition of the receptor endocytosis by BDNF, whereas the receptor reinsertion into the plasma membrane remains unaltered. Thus, GABA A R 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.

GABA Promotes Human β-Cell Proliferation and Modulates Glucose Homeostasis

“…Activation of GABA A R allows movement of Cl 2 in or out of the cells, thus modulating membrane potentials (25). In developing neurons, GABA induces depolarizing effects that result in Ca 2+ influx and activation of Ca 2+ -dependent signaling events involving PI3K (26) in modulating a variety of cellular processes such as proliferation and differentiation (8). Here, we report that GABA induces membrane depolarization and promotes calcium influx into b-cells.…”

Mechanism of BDNF Modulation in GABAergic Synaptic Transmission in Healthy and Disease Brains

“…In immature cultured rat hippocampal and hypothalamic neurons, the BDNF/TrkB dependent increase in GABA A Rs plasma membrane expression occurs when activation of GABA A Rs lead to a depolarization of the membrane potential, which in turn triggers the release of BDNF (Obrietan et al, 2002; Porcher et al, 2011). In more mature cultured rat hippocampal neurons and murine cerebellar granule cells, BDNF decreases the plasma membrane expression of GABA A Rs (Brünig et al, 2001; Cheng and Yeh, 2003).…”

Brain-derived neurotrophic factor increases the motility of a particular N-methyl-d-aspartate /GABA-responsive subset of neural progenitor cells

“…Several studies suggest a role for GABA in migration and differentiation (reviewed in Nguyen et al, 2001;Hagg, 2005;Sclett, 2006;Ge et al, 2007;Nakamichi et al, 2009). A connection between neurotrophin and glutamate/GABA signaling pathways is suggested as glutamate and GABA induce the expression of BDNF (Mattson, 2008;Porcher et al, 2011).…”