Modulation of TASK-1/3 channels at the hypoglossal motoneuron pool and effects on tongue motor output and responses to excitatory inputs in vivo: implications for strategies for obstructive sleep apnea pharmacotherapy
| Autor: | Richard L. Horner, Patrick Gurges, Hattie Liu |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
medicine.medical_specialty
Hypoglossal Nerve Basic Science of Sleep and Circadian Rhythms Tonic (physiology) 03 medical and health sciences Mice TASK channels 0302 clinical medicine Tongue Physiology (medical) Internal medicine medicine Premovement neuronal activity Animals Cholinergic neuron Rats Wistar AcademicSubjects/MED00385 sleep obstructive sleep apnea 030304 developmental biology Motor Neurons 0303 health sciences Sleep Apnea Obstructive Genioglossus Chemistry AcademicSubjects/SCI01870 animal model Rats upper airway medicine.anatomical_structure Endocrinology genioglossus Excitatory postsynaptic potential Wakefulness Neurology (clinical) Serotonin 030217 neurology & neurosurgery AcademicSubjects/MED00370 |
| Zdroj: | Sleep |
| ISSN: | 1550-9109 |
| Popis: | Obstructive sleep apnea (OSA) occurs exclusively during sleep due to reduced tongue motor activity. Withdrawal of excitatory inputs to the hypoglossal motor nucleus (HMN) from wake to sleep contributes to this reduced activity. Several awake–active neurotransmitters with inputs to the HMN (e.g. serotonin [5-HT]) inhibit K+ leak mediated by TASK-1/3 channels on hypoglossal motoneurons, leading to increased neuronal activity in vitro. We hypothesize that TASK channel inhibition at the HMN will increase tongue muscle activity in vivo and modulate responses to 5-HT. We first microperfused the HMN of anesthetized rats with TASK channel inhibitors: doxapram (75 μM, n = 9), A1899 (25 μM, n = 9), ML365 (25 μM, n = 9), acidified artificial cerebrospinal fluid (ACSF, pH = 6.25, n = 9); and a TASK channel activator terbinafine (50 μM, n = 9); all with and without co-applied 5-HT (10 mM). 5-HT alone at the HMN increased tongue motor activity (202.8% ± 45.9%, p < 0.001). However, neither the TASK channel inhibitors, nor activator, at the HMN changed baseline tongue activity (p > 0.716) or responses to 5-HT (p > 0.127). Tonic tongue motor responses to 5-HT at the HMN were also not different (p > 0.05) between ChAT-Cre:TASKf/f mice (n = 8) lacking TASK-1/3 channels on cholinergic neurons versus controls (n = 10). In freely behaving rats (n = 9), microperfusion of A1899 into the HMN increased within-breath phasic tongue motor activity in wakefulness only (p = 0.005) but not sleep, with no effects on tonic activity across all sleep–wake states. Together, the findings suggest robust maintenance of tongue motor activity despite various strategies for TASK channel manipulation targeting the HMN in vivo, and thus currently do not support this target and direction for potential OSA pharmacotherapy. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|