The Long-Term Behavioural Effects of Maternal Creatine Supplementation in a Spiny Mouse Model of Birth Asphyxia

Introduction: Birth asphyxia-induced encephalopathy is a major cause of long-term neurological morbidity, including cognitive and motor deficits. A proposed treatment is maternal creatine supplementation for prophylactic neuroprotection. This study examined how maternal creatine supplementation with or without birth asphyxia affected the behaviour of spiny mice offspring. Methods: On day 20 of gestation (mid-gestation; term=39 days), dams were randomly allocated to either a daily diet containing 5% w/w creatine monohydrate or remained on standard rodent chow. On gestational day 38, dams underwent either control caesarean section where offspring were delivered and recovered immediately, or birth asphyxia whereby the pregnant uterus was excised and placed in a saline bath for 7.5 min, inducing global hypoxia. All offspring were then cross-fostered to a lactating dam. Behavioural assessments were then completed on recovered offspring from neonatal to adolescent/adult ages (postnatal day [PND]3–41) using the open-field, elevated plus maze and novel object recognition test was conducted. Results: Offspring that underwent birth asphyxia displayed locomotor deficits and increased anxiety-like behaviour at PND3-7 in the open-field test (p<0.05) and impaired novel object discrimination at PND18 (p<0.05). Antenatal creatine exposure reduced anxiety-like behaviour irrespective of asphyxia in pups at PND3, indicating an amelioration of the asphyxia-induced anxiety-like behaviour. In adolescence/adulthood, creatine and asphyxia-exposed offspring showed reduced object exploration (p<0.0001). Antenatal creatine led to sustained reductions in anxiety-like behaviour in the elevated plus maze at adolescence and increased body weight, regardless of birth asphyxia exposure (p<0.05). Conclusion: Antenatal creatine exposure following maternal dietary creatine supplementation decreased anxiety-like behaviour in spiny mice offspring. This change negated behavioural abnormalities caused by birth asphyxia in the neonatal period, though it may have broader influences on long-term emotional and information processing in offspring which warrants further investigation.