Oral Presentation ESA-SRB-APEG-NZSE 2022

Sex dependent disruptions to the dopaminergic, GABAergic and glutamatergic systems throughout development of preterm born guinea pigs (#142)

Roisin A Moloney 1 2 , Julia c Shaw 1 2 , Hannah K Palliser 1 2 , Rebecca M Dyson 3 4 , Max J Berry 3 4 , Jonathan J Hirst 1 2
  1. Mothers and Babies Research Program , Hunter Medical Research Institute , Newcastle , Nsw, Australia
  2. University of Newcastle, Newcastle , NSW, Australia
  3. Department of Paediatrics and Child Health , University of Otago, Otago, Wellington, New Zealand
  4. Centre for Translational Physiology , University of Otago, Otago, Wellington, New Zealand

Preterm birth is associated with a significantly increased risk of neurobehavioral disorders, in particular attention deficit hyperactivity disorder (ADHD) and anxiety. These disorders are associated with disruptions to key neurotransmitter systems, including the dopaminergic system, and the inhibitory GABAergic and excitatory glutamatergic balance. These neurotransmitters play critical roles that control cognition and behaviour, however, are sensitive to damage. Preterm birth results in the premature exposure to the ex-utero environment, as well as removal from the placentally derived inhibitory neurosteroids. We propose that these damages disrupt key neurotransmitter systems which leads to the development of neurobehavioral disorders.

Dunkin Hartley time-mated guinea pig dams were allocated to fetal collection (preterm fetal; GA62, or term fetal; GA68), preterm induction of labour (preterm neonate; corrected postnatal day 1, or preterm juvenile; corrected postnatal day 40), or spontaneous term labour (term neonate; 24hrs old, or term juvenile; postnatal day 40). Relative mRNA expression of key neurotransmitter receptors in the frontal cortex were quantified by RT-PCR.

Dopamine receptor 1 (DRD1) mRNA expression was reduced in preterm male fetuses, neonates and juveniles compared to term born (p=0.01, p=0.02, and p=0.01 respectively). GABAA receptor α6 subunit (GABRA6) expression was increased in preterm male and female neonates compared to term born (p=0.02, p=0.03 respectively). GABAA receptor α4 subunit (GABRA4) expression was reduced in preterm male and female juveniles compared to term born (p=0.02, p=0.03 respectively). Male and female preterm neonates had increased glutamate NMDA receptor subunit 3A (GRIN3A) expression compared to term born (p=0.01 and p=0.03 respectively).

This study showed that preterm birth resulted in altered expression of receptors in the dopaminergic, GABAergic, and glutamatergic pathways that persisted throughout infancy and into childhood. These long-term changes may contribute to increased incidences of neurobehavioral disorders following preterm birth. Further studies are required to determine the mechanisms underpinning these changes