Early postnatal maturation of GABA(A)-mediated inhibition in the brainstemrespiratory rhythm-generating network of the mouse

It is well established that GABA(A)-mediated postsynaptic potentials are ex citatory in many brain regions during embryonic and early postnatal life. T he pre-Botzinger complex (PBC) in the brainstem is an essential component o f the respiratory rhythm-generating network, where GABA(A)-mediated inhibit ion plays a critical role in generating a stable respiratory rhythm in adul t animals. In the present study, using the perforated patch technique, we i nvestigated the maturation of GABA(A) receptor-mediated effects on rhythmic ally active PBC neurons and on the motor output in slice preparations from P0-15 neonatal mice. The reversal potential of GABA(A) receptor-mediated cu rrent (EGABA-A) switched from depolarizing to hyperpolarizing within the fi rst postnatal week. EGABA-A was -13.7 +/- 9.8 mV at P0, then it changed to -44.8 +/- 7.0 mV at P2 and -71.5 +/- 6.8 mV at P4. Perfusion of bicarbonate -free saline has no detectable influence on EGABA-A, indicating that a lack of Cl- extrusion during P0-3 is mainly responsible for early GABA(A)-ergic excitation. At the network level, blockade of GABA(A) receptors with bicuc ulline did not significantly change the frequency of rhythmic bursts record ed from hypoglossal nerve roots before P3, whereas it increased the coeffic ient of variation. After P3, bicuculline increased burst frequency with lit tle effect on the coefficient of variation. Thus, chloride-mediated inhibit ion, which appears in PBC neurons after P3, coincides with the appearance o f GABA(A)-mediated modulation of the respiratory rhythm. GABA(A) receptor-a ctivated inhibition may therefore be necessary for frequency modulation in the respiratory network beginning on the fourth postnatal day in the mouse brainstem.