Abstract
Reduced tongue muscle tone precipitates obstructive sleep apnea (OSA), and activation of the tongue musculature can lessen OSA. The hypoglossal motor nucleus (HMN) innervates the tongue muscles but there is no pharmacological agent currently able to selectively manipulate a channel (e.g., Kir2.4) that is highly restricted in its expression to cranial motor pools such as the HMN. To model the effect of manipulating such a restricted target, we introduced a “designer” receptor into the HMN and selectively modulated it with a “designer” drug. We used cre-dependent viral vectors (AAV8-hSyn-DIO-hM3Dq-mCherry) to transduce hypoglossal motoneurons of ChAT-Cre+ mice with hM3Dq (activating) receptors. We measured sleep and breathing in three conditions: (i) sham, (ii) after systemic administration of clozapine-N-oxide (CNO; 1 mg/kg) or (iii) vehicle. CNO activates hM3Dq receptors but is otherwise biologically inert. Systemic administration of CNO caused significant and sustained increases in tongue muscle activity in non-REM (261 ± 33% for 10 hrs) and REM sleep (217 ± 21% for 8 hrs), both P < 0.01 versus controls. Responses were specific and selective for the tongue with no effects on diaphragm or postural muscle activities, or sleep-wake states. These results support targeting a selective and restricted “druggable” target at the HMN (e.g., Kir2.4) to activate tongue motor activity during sleep.
Highlights
Obstructive sleep apnea (OSA) is a common and serious breathing disorder characterized by repeated episodes of upper airway obstruction and asphyxia during sleep[1,2,3,4]
The present study identifies, in principle, if systemic ingestion of a drug that selectively manipulates a regionally restricted “druggable” target at the hypoglossal motor pool can sustain the activity, during sleep, of a muscle that is critical to obstructive sleep apnea (OSA) pathogenesis
Localized incorporation of Designer Receptor’s Exclusively Activated by Designer Drugs (DREADDs) into hypoglossal motoneurons allows us to model the restricted expression of a pharmacological target in this motor pool that is highly relevant to OSA pathogenesis
Summary
Obstructive sleep apnea (OSA) is a common and serious breathing disorder characterized by repeated episodes of upper airway obstruction and asphyxia during sleep[1,2,3,4]. The inward-rectifying potassium 2.4 channel (Kir2.4) is expressed almost exclusively in the cranial motor pools that modulate pharyngeal muscle tone, and not in other brain regions[14,15,16] This localized expression makes Kir2.4 a therapeutic target of high interest, but there are no currently available small molecules to modulate it[13,16]. The present study identifies, in principle, if systemic ingestion of a drug that selectively manipulates a regionally restricted “druggable” target at the hypoglossal motor pool can sustain the activity, during sleep, of a muscle that is critical to OSA pathogenesis. The results provide proof-of-principle to develop and test small molecules acting upon ‘natural’ drug targets that are locally expressed at the cranial motor pools relevant to OSA
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