Acute manipulation of serotonergic neurons alters the mouse neonatal response to homeostatic stressors.

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Many sudden infant death syndrome (SIDS) cases are associated medullary serotonergic (5-HT) neuron abnormalities. We hypothesize that these abnormalities impair infants from adequately responding to stressors, such as hypoxia and hypercapnia (asphyxia). In response to asphyxia, young mammals initiate the “autoresuscitation” reflex – a survival promoting mechanism aimed at restoring homeostasis. Deficiency in this reflex is a proposed mechanism for SIDS mortality. To test the acute role of 5-HT neurons in autoresuscitation, we applied a chemogenetic neuronal inhibition strategy to inducibly suppress the activity of 5-HT neurons in unanesthetized mouse pups. Specifically, we expressed the synthetic inhibitory G-protein coupled receptor, Di, selectively in 5-HT neurons using mice transgenic for the driver Pet1::Flpe and the conditional Di-expressing knock-in allele RC::FDi. Selective 5-HT neuron inhibition follows upon intraperitoneal CNO injection. Using head-out plethysmography, we measured cardiorespiratory responses to repeated episodes of anoxia-induced (97% N2/3% CO2) apnea following acute inhibition of 5-HT neuron activity in P8 mouse pups. After injection with CNO, Di-expressing pups, but not controls, exhibited altered homeostatic parameters prior to an anoxic challenge. Additionally failure to autoresuscitate after anoxic challenge was more pronounced in CNO/Di-triggered pups than in controls, and was associated with a longer time to restore homeostasis. Results suggest that acute suppression of 5-HT neuron firing in mouse pups leads to altered baseline cardiorespiratory homeostasis and abnormal cardiorespiratory recovery from anoxia.