Partial Raphe Dysfunction in Neurotransmission Is Sufficient to Increase Mortality after Anoxic Exposures in Mice at a Critical Period in Postnatal Development

Abstract

Sudden infant death syndrome (SIDS) cases often have abnormalities of the brainstem raphe serotonergic (5-HT) system. We hypothesize that raphe dysfunction contributes to a failure to autoresuscitate from multiple hypoxic events, leading to SIDS. We studied autoresuscitation in two transgenic mouse models in which exocytic neurotransmitter release was impaired via conditional expression of the light chain from tetanus toxin (tox) in raphe neurons expressing serotonergic bacterial artificial chromosome drivers Pet1 or Slc6a4. ,Tph2low or negative raphe cells. At P5, P8, and P12, "silenced" mice and controls were exposed to five, ϳ37 s bouts of anoxia. Mortality was 5-10 times greater in "silenced" pups compared with controls at P5 and P8 (p ϭ 0.001) but not P12, with cumulative survival not differing between experimental transgenic models. "Silenced" pups that eventually died took longer to initiate gasping (p ϭ 0.0001), recover heart rate (p ϭ 0.0001), and recover eupneic breathing (p ϭ 0.011) during the initial anoxic challenges. Variability indices for baseline breathing distinguished "silenced" from controls but did not predict mortality. We conclude that dysfunction of even a portion of the raphe, as observed in many SIDS cases, can impair ability to autoresuscitate at critical periods in postnatal development and that baseline indices of breathing variability can identify mice at risk.

Neural activity in the periaqueductal gray and other specific subcortical structures is enhanced when a selective serotonin reuptake inhibitor selectively prevents seizure‐induced sudden death in the DBA/1 mouse model of sudden unexpected death in epilepsy

“…This effect is consistent with previous findings that fluoxetine enhanced respiration in DBA/1 mice only after Sz were induced. 53 These findings differentiate the effect of fluoxetine treatment alone, which did not increase activity in any respiratory structure, from its action to prevent S-IRA and complement the results from the Sal+Sz+RA versus Flx+Sz comparison. Thus, seizure after fluoxetine treatment resulted in increased activity at auditory and SML structures, including PAG, midbrain RF, and other SML sites, which is consistent with the role of serotonin at those structures implicated in Sz, as well as arousal and respiration.…”

“…37,47 Fluoxetine-induced enhancement of activity occurred in certain SML network brain regions, including the amygdala, cuneiform nucleus, pontine RF, and substantia nigra, to the same degree regardless of whether seizure was induced, suggesting that these sites may play a less significant role in fluoxetine-mediated blockade of RA. 4,5,9,22,38,[52][53][54] Also, fluoxetine-induced increases in activity at respiratory structures may be critical to the effect of Sz on respiratory ROIs and support the importance of serotonin in the recovery of normal respiratory function. 51 Fluoxetine significantly elevated the activity at most of the ROIs previously implicated in the DBA/1 seizure network as well as in respiratory structures in the presence of Sz (Flx+Sz) as compared to fluoxetine's effects without seizure (Flx-noSz).…”

“…Thus, seizure after fluoxetine treatment resulted in increased activity at auditory and SML structures, including PAG, midbrain RF, and other SML sites, which is consistent with the role of serotonin at those structures implicated in Sz, as well as arousal and respiration. 4,5,9,22,38,[52][53][54] Also, fluoxetine-induced increases in activity at respiratory structures may be critical to the effect of Sz on respiratory ROIs and support the importance of serotonin in the recovery of normal respiratory function. 53 These findings differentiate the effect of fluoxetine treatment alone, which did not increase activity in any respiratory structure, from its action to prevent S-IRA and complement the results from the Sal+Sz+RA versus Flx+Sz comparison.…”

Pre‐ and early postnatal nicotine exposure exacerbates autoresuscitation failure in serotonin‐deficient rat neonates

“…; Barrett et al . ), with defects including prolonged apnoea or delayed onset of gasping and delayed restoration of eupnoea and heart rate. The reported deficiency of brainstem 5‐HT includes ∼26% in SIDS cases (Duncan et al .…”

“…), 35% in Pet1::Flpe‐silenced pups (Barrett et al . ), and over 80% in Pet‐1 −/− knockout mouse (Cummings et al . , ) and serotonin lesioned rat pups (Cummings et al .…”