Determining the mechanisms underlying a potential treatment for sleep apnea

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DESCRIPTION (provided by applicant): A profound and long-lasting facilitation of endogenously-generated, respiratory- related hypoglossal nerve activity in the neonatal rat medullary slice preparation has been discovered. It results from a 1-hour bath application of the AMPA receptor anti-desensitization drug cyclothiazide (CTZ). This phenomenon, termed CTZ-induced facilitation (CIF), consistently lasts >12 hours following the completion of drug application but does not depend upon activation of ionotropic glutamate receptors during administration of CTZ. This facilitation of hypoglossal nerve activity is triple that seen in another model of respiratory plasticity studied in this lab, in vitro long-term facilitation (ivLTF). Importantly, these observations are behaviorally relevant. Injection of CTZ into intact, isoflurane-anesthetized, adult rats facilitates the amplitude of phasic genioglossus (GG) muscle activity without affecting respiratory rate or heart rate. The mechanism underlying CIF is unknown. This project will test 3 mechanisms that, based on preliminary data, most likely underlie CIF, after characterizing the dynamics and intracellular effects of this phenomenon in greater detail. Aim 1 has two objectives: (i) determine whether the duration of CTZ application along with CTZ concentration determines the magnitude and time course of CIF; (ii) parse the effects of CTZ on the respiratory control circuit by focally applying CTZ to 3 regions in the slice known to affect respiratory rhythm. Aim 2 investigates how CTZ exposure modifies fast excitatory signaling, inhibitory signaling, and firing properties within hypoglossal motoneurons in the short and long terms, establishing a baseline intracellular response for testing the mechanisms hypothesized to underlie CIF. Aim 3 tests the mechanisms hypothesized to underlie CIF: (i) permanent abolition of AMPA receptor desensitization, (ii) direct intracellular action, (iii) disruption of constitutive AMPA receptor recycling. RELEVANCE: Obstructive sleep apnea (OSA) is a disease that affects as many as 1 in 5 adult Americans in varying degrees of severity. Currently, there is no pharmacological treatment for this disease; while, other methods of treatment are highly invasive and/or of limited effectiveness. An understanding of the mechanisms underlying facilitation of respiratory motor output to muscles of the tongue and upper airway will foster the development of effective, easy to use treatments improving the long-term health of millions.