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Differential ontogeny of GABA_B-receptor-mediated pre- and postsynaptic modulation of GABA and glycine transmission in respiratory rhythm-generating network in mouse

W. Zhang, A. Barnbrock, S. Gajic, A. Pfeiffer and B. Ritter

Rhythm generation in mature respiratory networks is influenced strongly by synaptic inhibition. In early neonates, GABA_A-receptor- and glycine-receptor-mediated inhibition is not present, thus the question arises as to whether GABA_B-receptor-mediated inhibition plays an important role. Using brainstem slices of neonatal mice (postnatal day, P0-P15), we analysed the role of GABA_B-mediated modulation of GABA and glycine synaptic transmission in the respiratory network. Blockade of GABA uptake by nipecotic acid (0.25-2 mM) reduced the respiratory frequency. This reduction was prevented by the selective GABA_B receptor antagonist CGP55845A (CGP) alone at P0-P3, but by bicuculline as well as CGP at P7-P15. Blockade of GABA_B receptors by CGP increased the respiratory frequency at P0-P3, whereas it caused a reduction of frequency in older animals. The effect of CGP on respiratory frequency was diminished in the presence of bicuculline and strychnine in older but not in younger animals. The relative contribution of GABA_B-receptor-mediated pre- and postsynaptic modulation was examined by analysing the effect of GABA_B receptors on spontaneous and miniature IPSCs. In younger animals (P0-P3), the GABA_B receptor agonist baclofen had no detectable effect on IPSC frequency, but caused a significant decrease in the amplitude. In older animals (P7-P15), baclofen decreased both the frequency and amplitude of spontaneous and miniature IPSCs. These results demonstrate that GABA_B-receptor-mediated postsynaptic modulation plays an important role in the respiratory network from P0 on. GABA_B-receptor-mediated presynaptic modulation develops with a longer postnatal latency, and becomes predominant within the first postnatal week.

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