Differential ontogeny of GABA_Breceptor‐mediated pre‐ and postsynaptic modulation of GABA and glycine transmission in respiratory rhythm‐generating network in mouse

Abstract

Rhythm generation in mature respiratory networks is influenced strongly by synaptic inhibition. In early neonates, GABAA‐receptor‐ and glycine‐receptor‐mediated inhibition is not present, thus the question arises as to whether GABAB‐receptor‐mediated inhibition plays an important role. Using brainstem slices of neonatal mice (postnatal day, P0‐P15), we analysed the role of GABAB‐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 GABAB receptor antagonist CGP55845A (CGP) alone at P0‐P3, but by bicuculline as well as CGP at P7‐P15. Blockade of GABAB 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 GABAB‐receptor‐mediated pre‐ and postsynaptic modulation was examined by analysing the effect of GABAB receptors on spontaneous and miniature IPSCs. In younger animals (P0‐P3), the GABAB 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 GABAB‐receptor‐mediated postsynaptic modulation plays an important role in the respiratory network from P0 on. GABAB‐receptor‐mediated presynaptic modulation develops with a longer postnatal latency, and becomes predominant within the first postnatal week.

Arrest of 5HT neuron differentiation delays respiratory maturation and impairs neonatal homeostatic responses to environmental challenges

“…Since catecholaminergic neurons in this region receive serotonergic synaptic input (Pickel et al, 1984), it is possible that the effects we have observed in 5HT neuron-deficient Pet-1 −/− mice are indirect and result from the loss of 5HT modulation of noradrenergic influences on central rhythm generation. In addition, a developmental switch from excitatory to inhibitory γ-aminobutyric acid (GABA)-mediated neurotransmission has been shown to occur in mouse preBötC neurons during the first postnatal week (Ritter and Zhang, 2000;Zhang et al, 2002). Since serotonergic inputs have been shown to delay the maturation of inhibitory (GABAergic) influences on developing rhythmic circuits in the spinal cord (Branchereau et al, 2002;Allain et al, 2005), it is conceivable that the loss of 5HT neuron function results in premature switching to GABA-mediated inhibitory inputs to the respiratory central pattern generator, resulting in a longer period of depressed and unstable breathing in Pet-1 −/− mice.…”

“…Several neurotransmitters including glutamate, substance P, GABA, and noradrenaline are known to influence respiratory network activity during these periods of respiratory maturation (Ritter and Zhang, 2000;Zhang et al, 2002;Hilaire et al, 2004;Thoby-Brisson et al, 2005;Hilaire, 2006;Zanella et al, 2006). In addition, a preponderance of physiological data indicate that respiratory drive is increased by exogenously applied serotonin (5HT) agonists or stimulation of endogenous 5HT release during the perinatal period, both in vivo and in vitro (for review, see Hilaire and Duron, 1999;Richerson, 2004).…”

Subcellular vesicular aggregations of GABAB R1a and R1b receptors increase with age in neurons of the developing mouse brain

“…At early post-natal stages, GABA A receptormediated synaptic inhibition is functionally not present in many brain regions (Ballanyi and Grafe 1985;Cherubini et al 1991;Hara et al 1992;Gaiarsa et al 1995;Ritter and Zhang 2000). During the same period, GABA B receptors are not only functional (Cherubini et al 1991;Gaiarsa et al 1995), but they also seem to play a critical role in the synaptic modulation (Zhang et al 2002). Whereas GABA B receptors in adult animals exert both pre-synaptic and post-synaptic inhibitory effects (Misgeld et al 1995), during the early post-natal stage the inhibitory effects of GABA B receptor activation are either solely pre-synaptic, as shown in the rat hippocampus (Gaiarsa et al 1995), or post-synaptic, as shown in the brain stem of the mouse (Zhang et al 2002).…”

“…Such information would be valuable for relating changes in cellular localisation and subcellular receptor trafficking of GABA B receptors to alterations in the functional role of GABA B receptors during post-natal development (Gaiarsa et al 1995;Zhang et al 2002). In the present study, specific antibodies were used to determine the cellular and subcellular localisations of GABA B R1 receptors in different brain regions of mice during post-natal development (P0-P66).…”

“…During the same period, GABA B receptors are not only functional (Cherubini et al 1991;Gaiarsa et al 1995), but they also seem to play a critical role in the synaptic modulation (Zhang et al 2002). Whereas GABA B receptors in adult animals exert both pre-synaptic and post-synaptic inhibitory effects (Misgeld et al 1995), during the early post-natal stage the inhibitory effects of GABA B receptor activation are either solely pre-synaptic, as shown in the rat hippocampus (Gaiarsa et al 1995), or post-synaptic, as shown in the brain stem of the mouse (Zhang et al 2002). Light-microscopic immunocytochemical study has shown that the immunoreactivity for GABA B R1 and R2 is differentially distributed in the rat neocortex during perinatal periods (Lopez-Bendito et al 2002).…”