Although extracellular calcium ionic concentration ([Ca]o) is known to increase during late gestation and to drop after parturition, little is known about the influence of [Ca]o on fetal brain function. We have investigated the influence of [Ca]o, calcium-sensing receptors/nonselective cation currents (CaSR/NSCC), and GABAergic inhibitions on maturation of brainstem-spinal motor activities: the primary low-frequency embryonic rhythm [LF; silent since embryonic day (E)16] and the fetal respiratory rhythm (RR; emerging at E14–E15). Using in vitro isolated brainstem-spinal cord preparations of mice at different fetal and postnatal (P) stages (E16–P1), we demonstrate that reducing fetal [Ca]o from 1.2 mM to 0.7 mM at E16–E18 or blocking GABAA receptors at E16–P0 reactivates LF and reveals LF-related disturbance of RR at E16–E18. This LF is stopped by adding gadolinium or spermidine (CaSR/NSCC agonists) at E18–P0 or GABAA receptor agonists at E16–E18. In contrast, [Ca]o–induced slowing of RR at E16–E18 is not reproduced by gadolinium and spermidine. We conclude that perinatal CaSR/NSCC and GABAA inhibition allow quiescence of the LF, thereby improving functional maturation of the RR. © 2010 Wiley-Liss, Inc.