Roles of taurine-mediated tonic GABAA receptor activation in the radial migration of neurons in the fetal mouse cerebral cortex

gamma-Aminobutyric acid (GABA) depolarizes embryonic cerebrocortical neurons and continuous activation of the GABA(A) receptor (GABA(A)R) contributes to their tonic depolarization. Although multiple reports have demonstrated a role of GABA(A)R activation in neocortical development, including in migration, most of these studies have used pharmacological blockers. Herein, we performed in utero electroporation in GABA synthesis-lacking homozygous GAD67-GFP knock-in mice (GAD67(GFP/GFP)) to label neurons born in the ventricular zone. Three days after electroporation, there were no differences in the distribution of labeled cells between the genotypes. The dose response properties of labeled cells to GABA were equivalent among genotypes. However, continuous blockade of GABA(A)R with the GABA(A)R antagonist SR95531 accelerated radial migration. This effect of GABA(A)R blockade in GAD67(GFP/GFP) mice suggested a role for alternative endogenous GABA(A)R agonists. Thus, we tested the role of taurine, which is derived from maternal blood but is abundant in the fetal brain. The taurine-evoked currents in labeled cells were mediated by GABA(A)R. Taurine uptake was blocked by a taurine transporter inhibitor, 2-(guanidino)ethanesulfonic acid (GES), and taurine release was blocked by a volume-sensitive anion channel blocker, 4-(2-butyl-6,7-dichlor-2-cyclopentylindan-1-on-5-yl) oxobutyric acid, as examined through high-performance liquid chromatography. GES increased the extracellular taurine concentration and induced an inward shift of the holding current, which was reversed by SR95531. In a taurine-deficient mouse model, the GABA(A)R-mediated tonic currents were greatly reduced, and radial migration was accelerated. As the tonic currents were equivalent among the genotypes of GAD67-GFP knock-in mice, taurine, rather than GABA, might play a major role as an endogenous agonist of embryonic tonic GABA(A)R conductance, regulating the radial migration of neurons in the developing neocortex.