Time- and age-dependent effects of serotonin on gasping and autoresuscitation in neonatal mice

The role of brain stem serotonin (5-hydroxytryptamine, 5-HT) in autoresuscitation in neonatal life is unclear. We hypothesized that a specific loss of 5-HT would compromise gasping and autoresuscitation mainly in the second postnatal week and that acute restoration of 5-HT would reverse the defects. We exposed postnatal day (P)4-5, P8-9, and P11-12 tryptophan-hydroxylase-2 knockout (TPH2(-/-)) and wild-type littermates (WT) to 10 episodes of anoxia (97% N-2, 3% CO2), measuring survival, gasp latency, gasp frequency (f(B)), and the time required to restore eupnea and heart rate. We also tested P8-9 TPH2(-/-) mice after restoring 5-HT with a single injection of 5-hydroxytryptophan (5-HTP) 1-2 h before testing or with multiple injections beginning 24 h before testing. At P4-5 and P8-9, but not at P11-12, gasp latency and the recovery of eupnea were delayed similar to 2-to 3-fold in TPH2(-/-) pups compared with WT (P < 0.001). At all ages, TPH2(-/-) pups displayed reduced gasp f(B) (similar to 20-30%; P < 0.001) and delayed heart rate recovery (similar to 60%; P = 0.002) compared with WT littermates. TPH2(-/-) survival was reduced compared with WT (P < 0.001), especially at P8-9 and P11-12 (P = 0.004). Whereas 1-2 h of 5-HTP treatment improved the gasp latency and f(B) of P8-9 TPH2(-/-) pups, improved cardiorespiratory recovery and survival required 24 h of treatment. Our data suggest that 5-HT operates over a long time span (similar to 24 h) to improve survival during episodic severe hypoxia. Early in development (P4-9), 5-HT is critical for both respiratory and cardiovascular components of autoresuscitation; later (P11-12), it is critical mainly for cardiovascular components. Nevertheless, the effect of 5-HT deficiency on survival is most striking from P8 to P12.