Silencing vesicular neurotransmission in medullary serotonergic (5HT) neurons causes prolonged and failed autoresuscitation during early postnatal life in mice: possible implications for the sudden infant death syndrome (SIDS)

Abstract

Abnormalities in the medullary 5HT system, including decreased tissue levels of 5HT, have been identified in approximately 70% of SIDS cases studied. Failed autoresuscitation (inability to recover breathing and heart rate following hypoxic apnea) is considered a possible cause of death in SIDS infants. Using 5HT ‘silenced’ mice, we examined the effect of altered neurotransmitter release from 5HT neurons on the ability to autoresuscitate after repeated exposure to intermittent anoxia at postnatal days (P) 5, 8 and 12. In these mice, Cre recombinase activates expression of tetanus toxin light chain in medullary 5HT neurons, which cleaves the VAMP2 protein that anchors vesicles to the synaptic membrane, thus suppressing synaptic vesicular neurotransmission in these neurons. ‘Silenced’ pups took twice as long as controls to initiate gasping at P5 and P8, and had a 22% reduction in gasp frequency at P8. Recovery of heart rate and breathing to 90% of normal was prolonged up to 5 and 2 times, respectively compared to controls at P8. Autoresuscitation failed in 19% of the ‘silenced’ pups at P5 and 44% at P8, compared to no control pup deaths. These data indicate that suppressing vesicular neurotransmission in 5HT neurons delays initiation of gasping and suggest that this may contribute to prolonged or failed autoresuscitation in response to anoxia in early postnatal life. (HD036379)