Non-hyperpolarizing GABA_B receptor activation regulates neuronal migration and neurite growth and specification by cAMP/LKB1

γ-Aminobutyric acid is the principal inhibitory neurotransmitter in adults, acting through ionotropic chloride-permeable GABA_A receptors (GABA_A Rs), and metabotropic GABA_B Rs coupled to calcium or potassium channels, and cyclic AMP signalling. During early development, γ-aminobutyric acid is the main neurotransmitter and is not hyperpolarizing, as GABA_A R activation is depolarizing while GABA_B Rs lack coupling to potassium channels. Despite extensive knowledge on GABA_A Rs as key factors in neuronal development, the role of GABA_B Rs remains unclear. Here we address GABA_B R function during rat cortical development by in utero knockdown (short interfering RNA) of GABA_B R in pyramidal-neuron progenitors. GABA_B R short interfering RNA impairs neuronal migration and axon/dendrite morphological maturation by disrupting cyclic AMP signalling. Furthermore, GABA_B R activation reduces cyclic AMP-dependent phosphorylation of LKB1, a kinase involved in neuronal polarization, and rescues LKB1 overexpression-induced defects in cortical development. Thus, non-hyperpolarizing activation of GABA_B Rs during development promotes neuronal migration and morphological maturation by cyclic AMP/LKB1 signalling.