Our long-term objective is to understand postnatal development of fast ligand-gated inhibitory (both GABAergic) and glycinergic) synaptic transmission to an important class of respiratory motoneurons, the hypoglossal motoneurons (HM). HMs innervate the tongue and therefore are important in the regulation of upper airway patency. The upper airway is a site of airway obstruction; thus a full understanding of the development of synaptic inhibition to HMs may provide new insights into certain pathologic states, including apnea of prematurity, Sudden Infant Death Syndrome and obstructive sleep apnea. The experiments proposed use two different in vitro brainstem slice preparations. In one rat, HMs will be visualized and studied with whole-cell and outside patch recordings in the absence of respiratory rhythm. The other uses the mouse rhythmic medullary slice preparation to study short-time-scale synchronization of inspiratory-phase HM activity.
Specific Aim 1 proposes to investigate developmental changes that occur in GABAergic synaptic currents in HMs, as well as in single GABAA receptor channel properties. We hypothesize that developmental changes in GABAergic synaptic transmission are due to changes in properties of this ligand-gated ion channel.
Specific Aim 1 proposes to investigate developmental changes and mechanisms for modulation by EtOH of GABAergic synaptic transmission to HMs. We hypothesize that in HMs the potentiation of GABAergic synaptic events by EtOH is due to altered single channel kinetics of GABAA-Rs.
Specific Aim 3 proposes to investigate the postnatal developmental changes that occur in GABAA presynaptic receptor inhibition of GABAergic and glycinergic synaptic transmission. We hypothesize that this inhibition is dependent on postnatal age and is significantly enhanced in older HMs.
In Specific Aim 4 we propose to investigate, in the rhythmic medullary slice preparation, short-time-scale synchronous HM inspiratory-phase activity, and to determine the role of GABAA-R and glycine-R activation in the postnatal development of this activity. We hypothesize that changes in sub-unit composition of both these receptors and intracellular chloride ion regulation leads to effects upon short-time-scale HM synchronized activity that are developmentally dependent.
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