Role of fast inhibitory synaptic transmission in neonatal respiratory rhythmogenesis and pattern formation

Several studies have investigated the general role of chloride-based neurotransmission (GABA_A and glycinergic signaling) in respiratory rhythmogenesis and pattern formation. In several brain regions, developmental alterations in these signaling pathways have been shown to be mediated by changes in cation-chloride cotransporter (CC) expression. For instance, CC expression changes during the course of neonatal development in medullary respiratory nuclei and other brain/spinal cord regions in a manner which decreases the cellular import, and increases the export, of chloride ions, shifting reversal potentials for chloride to progressively more negative values with maturation. In slice preparations of the same, this is related to an excitatory-to-inhibitory shift of GABA_A- and glycinergic signaling. In medullary slices, GABA_A-/glycinergic signaling in the early neonatal period is excitatory, becoming inhibitory over time. Additionally, blockade of the Na⁺/K⁺/2Cl⁻ cotransporter, which imports these ions via secondary active transport, converts excitatory response to inhibitory ones. These effects have not yet been demonstrated at the individual respiratory-related neuron level to occur in intact (in vivo or in situ) animal preparations, which in contrast to slices, possess normal network connectivity and natural sources of tonic drive. Developmental changes in respiratory rhythm generating and pattern forming pontomedullary respiratory circuitry may contribute to critical periods, during which there exist increased risk for perinatal respiratory disturbances of central, obstructive, or hypoxia/hypercapnia-induced origin, including the sudden infant death syndrome. Thus, better characterizing the neurochemical maturation of the central respiratory network will enhance our understanding of these conditions, which will facilitate development of targeted therapies for respiratory disturbances in neonates and infants.