Bilirubin Triggers Calcium Elevations and Dysregulates Giant Depolarizing Potentials During Rat Hippocampus Maturation

Neonatal hyperbilirubinemia may result in long-lasting motor, auditory and learning impairments. The mechanisms responsible for the localization of unconjugated bilirubin (UCB) to specific brain areas as well as those involved in potentially permanent central nervous system (CNS) dysfunctions are far from being clear. One area of investi- gation includes exploring how hyperbilirubinemia determines neuronal alterations pre- disposing to neurodevelopmental disorders. We focused on the hippocampus and pyram- idal cell dysregulation of calcium homeostasis and synaptic activity, with a particular fo- cus on early forms of correlated network activity, i.e., giant depolarizing potentials (GDPs), crucially involved in shaping mature synaptic networks. We performed live cal- cium imaging and patch clamp recordings from acute hippocampal slices isolated from wild-type rats exposed to exogenous high bilirubin concentration. We then explored the impact of endogenous bilirubin accumulation in hippocampal slices isolated from a ge- netic model of hyperbilirubinemia, i.e., Gunn rats. Our data show in both models an age- dependent dysregulation of calcium dynamics accompanied by severe alterations in GDPs, which were strongly reduced in hippocampal slices of hyperbilirubinemic rats, where the expression of GABAergic neurotransmission markers was also altered. We pro- pose that hyperbilirubinemia damages neurons and affects the refinement of GABAergic synaptic circuitry during a critical period of hippocampal development.