Proceedings of The Physiological Society

Physiology 2016 (Dublin, Ireland) (2016) Proc Physiol Soc 37, PCB263

Poster Communications

Secretions from the placenta alter neuronal development after hypoxic insult during pregnancy

T. Phillips1, J. Morton2, C. Cooke2, S. Davidge2, P. Case1

1. University of Bristol, Bristol, United Kingdom. 2. University of Alberta, Edmonton, Alberta, Canada.

Psychological disorders such as autism, schizophrenia and ADD are thought to originate partially due to insults to the foetus during pregnancy. Events such as hypoxia reoxygenation during pregnancy have been shown to increase the risk of psychological disorders in later life. While the placenta normally acts as a protective barrier between the mother and the foetus we have found during a hypoxic insult it releases damaging molecules into the foetal circulation. We modelled obstetric complication and exposed a placental trophoblast barrier model or ex vivo placental explants to variable oxygen levels. We collected tissue culture media from below the barrier and analysed its contents. We found that the placental barrier secreted increased levels of glutamate (4x increase) when exposed to hypoxia and hypoxia/reoxygenation. Previous experiments1 demonstrated that this media when directly exposed to E18 rat neurone cultures or injected directly into P4 rat brains was able to alter neurones, astrocytes and NMDA receptors in vitro and in vivo. To investigate if these changes were maintained without direct exposure experiments performed in collaboration with Professor Davidge's group in the University of Alberta were performed using their established model of Maternal Hypoxia. In this model pregnant rats (n=3) were placed in 11% Oxygen on GD15 for 6 days then the brains of their offspring were examined at P30 (four per litter). These brains demonstrated a reduction in Parvalbumin positive cells (353+/-96 vs 304+/-64 cells per FOV +/-S.D p < 0.05 One way ANOVA), increased TH+ process (7839+/-252 vs 10745+/-236 µm per FOV +/-S.D p < 0.001 One way ANOVA), loss of dendrite length (5995+/-950 vs 3708+/-584 µm per FOV +/-S.D p < 0.001 One way ANOVA) and reduced detection of GluN1 (2000+/-694 vs 1503+/-400 pixel per FOV+/-S.D p < 0.05 One way ANOVA) in the thalamic reticular nucleus and cortex. We have attempted to negate the changes caused by maternal hypoxia by treating the mother's placenta with one injection on GD15 of MitoQ bound to a γPGA nanoparticle (90.08µg/Kg) to prevent the changes in the placenta secretions. This treatment has proven to be successful in preventing the changes in dendrite length and NMDA receptors in vitro and changes to neurones and receptors in vivo. This nanoparticle treatment was also able to prevent the loss of offspring birth weight associated with maternal hypoxia (7.1g+/-0.2 vs 5.8g+/-0.34 S.D p < 0.001 One way ANOVA). Our hypothesis is that factors including glutamate, released from the placenta during hypoxia might enter the foetal circulation and cause changes in the developing brain. These changes are similar to the types of changes seen in post mortem brains of patients with Schizophrenia and can be prevented by treatment of the placenta with MitoQ bound to nanoparticles.

Where applicable, experiments conform with Society ethical requirements