Postnatal development of persistent inward currents in rat XII motoneurons and their modulation by serotonin, muscarine and noradrenaline

Abstract

Key points Persistent inward currents (PICs) in spinal motoneurons are long‐lasting, voltage‐dependent currents that increase excitability; they are dramatically potentiated by serotonin, muscarine, and noradrenaline (norepinephrine). Loss of these modulators (and the PIC) during sleep is hypothesized as a major contributor to REM sleep atonia. Reduced excitability of XII motoneurons that drive airway muscles and maintain airway patency is causally implicated in obstructive sleep apnoea (OSA), but whether XII motoneurons possess a modulator‐sensitive PIC that could be a factor in the reduced airway tone of sleep is unknown. Whole‐cell recordings from rat XII motoneurons in brain slices indicate that PIC amplitude increases ∼50% between 1 and 23 days of age, when potentiation of the PIC by 5HT2, muscarinic, or α1 noradrenergic agonists peaks at <50%, manyfold lower than the potentiation observed in spinal motoneurons. α1 noradrenergic receptor activation produced changes in XII motoneuron firing behaviour consistent with PIC involvement, but indicators of strong PIC activation were never observed; in vivo experiments are needed to determine the role of the modulator‐sensitive PIC in sleep‐dependent reductions in airway tone. Abstract Hypoglossal (XII) motoneurons play a key role in maintaining airway patency; reductions in their excitability during sleep through inhibition and disfacilitation, i.e. loss of excitatory modulation, is implicated in obstructive sleep apnoea. In spinal motoneurons, 5HT2, muscarinic and α1 noradrenergic modulatory systems potentiate persistent inward currents (PICs) severalfold, dramatically increasing excitability. If the PICs in XII and spinal motoneurons are equally sensitive to modulation, loss of the PIC secondary to reduced modulatory tone during sleep could contribute to airway atonia. Modulatory systems also change developmentally. We therefore characterized developmental changes in magnitude of the XII motoneuron PIC and its sensitivity to modulation by comparing, in neonatal (P1–4) and juvenile (P14–23) rat brainstem slices, the PIC elicited by slow voltage ramps in the absence and presence of agonists for 5HT2, muscarinic, and α1 noradrenergic receptors. XII motoneuron PIC amplitude increased developmentally (from −195 ± 12 to −304 ± 19 pA). In neonatal XII motoneurons, the PIC was only potentiated by α1 receptor activation (5 ± 4%). In contrast, all modulators potentiated the juvenile XII motoneurons PIC (5HT2, 5 ± 5%; muscarine, 22 ± 11%; α1, 18 ± 5%). These data suggest that the influence of the PIC and its modulation on XII motoneuron excitability will increase with postnatal development. Notably, the modulator‐induced potentiation of the PIC in XII motoneurons was dramatically smaller than the 2‐ to 6‐fold potentiation reported for spinal motoneurons. In vivo measurements are required to determine if the modulator‐sensitive, XII motoneuron PIC is an important factor in sleep‐state dependent reductions in airway tone.

Chronic intermittent hypoxia increases excitability and synaptic excitation of protrudor and retractor hypoglossal motoneurones

“…It is worth mentioning the differences in the animals' age (neonatal vs. juvenile) and applied experimental approaches (medullary slices vs. brainstem-spinal cord preparation) between the studies. Therefore, it is possible that CIH affects the well-described post-natal development of the hypoglossal motoneurones' electrophysiological properties (Funk et al 1997;Revill et al 2019) or even that these motoneurones are more susceptible to the deleterious effects of CIH in neonatal rats. Besides, the presence of protrudor and retractor pre-motor neurones in our in situ experimental approach, such as in the Kölliker-Fuse, parabrachial nucleus and nucleus of the solitary tract (Dobbins & Feldman, 1995), could also contribute to the different effects of CIH on the inspiratory-related synaptic excitation to hypoglossal motoneurones observed between the studies.…”

Receptor-independent membrane mediated pathways of serotonin action

“…The neurotransmitter serotonin, in addition to its directed action through synaptic signaling, has an indirect neuro-modulatory role [11][12][13][14][15][16] . A significant amount of serotonin is released from extrasynaptic areas, including from the cell body, away from the site of post-synaptic receptor densities 6,7,[17][18][19] .…”

Gut-Brain Axis: Probiotic,Bacillus subtilis, Prevents Aggression via the Modification of the Central Serotonergic System

“…Gut-Brain Axis: Probiotic, Bacillus subtilis, Prevents Aggression via the Modification… DOI: http://dx.doi.org/10.5772/intechopen.86775 [91][92][93][94] and social behavior [95,96], affecting mental health [97][98][99][100] and providing therapeutic strategy for treating or preventing stress reaction and related neuropsychiatric disorders [94,97].…”