Our long-term objective is to understand how respiratory-related neurons synaptically interact. This application focuses on glycine and gamma-aminobutyric acid (GABA) ligand-gated receptors (glycine-Rs and GABAA-Rs, respectively). We hypothesize that they are important in brainstem and spinal cord physiology related to the neurobiology of breathing. The upper airway is a site of airway obstruction: thus understanding of synaptic transmission to hypoglossal motoneurons (HMs) may provide new insights into airway pathologies such as obstructive sleep apnea. We continue to focus our research on HMs because the tongue has a critical position in the upper airway, thereby affecting upper airway resistance and patency. Also, HMs are important in other behaviors including mastication, swallowing (deglutition), sucking, licking, and vocalization. The experiments proposed employ two different in vitro brainstem slice preparations to study glycinergic and GABAergic synaptic transmission to HMs. In both, rat HMs will be visualized using infra-red differential interference optics and we will use whole-cell and outside-out patch recordings from these neurons. HMs will be studied in the absence (standard slice preparation) and in the presence (rhythmic slice preparation) of ongoing rhythmic respiratory activity.
Specific aim 1 proposes to characterize GABAA -R-mediated synaptic transmission to HMs. We hypothesize that GABAA-Rs have differential pharmacological and kinetic properties as compared to glycine-Rs.
Specific Aim 2 proposes to investigate glycine and GABA cotransmission at individual synaptic terminals apposed to HMs. We hypothesize that glycine and GABA are co-released and that following co-release they activate co-localized glycine and GABAA receptors at individual synaptic terminals.
Specific Aim 3 proposes to investigate whether glycine and/or GABAA receptor mediated synaptic events are important for the respiratory-related behavior of HMs recorded in the rhythmic medullary slice preparation. We hypothesize that glycine and/or GABA mediated synaptic events shape the inspiratory phase behavior of HMs, mostly via shunting inhibition of excitatory respiratory drive. The fourth Specific Aim proposes to investigate in HMs postsynaptic mechanisms whereby ethanol modulates glycine-Rs. We hypothesize that ethanol increases the affinity of glycine-Rs for glycine and thereby potentiates inhibitory synaptic events. This may be an important mechanism whereby alcohol consumption exacerbates obstructive sleep apnea.
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