Neonatal mice lacking serotonin neurons have high mortality that is worsened on exposure to hypoxia and hypercapnia.

Abstract

Lmx1bf/f/p mice, which selectively lack central serotonin (5‐HT) neurons, have respiratory abnormalities, high mortality and growth retardation in the perinatal period. Here we studied the effects on mortality and growth rate of raising neonatal WT and Lmx1bf/f/p mice from ages P0‐P21 in environments containing 21% O2, 10% O2, 10% O2 & 5% CO2 or 50% O2. Lmx1bf/f/p mice had lower growth rate compared to WT in the same gas condition. Interestingly, WT mice raised in hypoxia grew at a rate equivalent to Lmx1bf/f/p mice raised in normoxia, whereas hypoxia further reduced growth of Lmx1bf/f/p mice. ANOVA revealed a significant effect of age (p < 0.001) and gas conditions (p < 0.001). Moreover, there was high perinatal mortality of Lmx1bf/f/p mice in normoxia that was worsened by hypoxia and improved by hyperoxia. The expected Mendelian ratio of the two genotypes (KO/WT) at the time litters were discovered should have been 1, but it was 0.48 in normoxia, 0.29 in hypoxia, 0.55 in hypoxic‐hypercapnia and 1.54 in hyperoxia. Kaplan‐Meier curves showed continued excess mortality in Lmx1bf/f/p mice for the first 3 postnatal days. Postnatal mortality was also worsened with hypoxia and improved with hyperoxia. Our results indicate that a defect in the 5‐HT system creates heightened vulnerability to hypoxia in neonatal mice, which could be related to the ventilatory abnormalities and vulnerability to exogenous stressors of SIDS infants.