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

## TL;DR

High bilirubin levels in newborn rats disrupt brain development by altering calcium levels and neural activity in the hippocampus.

## Contribution

This study reveals how hyperbilirubinemia disrupts hippocampal development through calcium dysregulation and altered GABAergic signaling.

## Key findings

- High bilirubin levels in rats cause age-dependent calcium dysregulation in the hippocampus.
- Hyperbilirubinemia reduces giant depolarizing potentials and alters GABAergic markers in developing hippocampal slices.
- Both exogenous and endogenous bilirubin models show similar impairments in synaptic network development.

## Abstract

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 investigation includes exploring how hyperbilirubinemia determines neuronal alterations predisposing to neurodevelopmental disorders. We focused on the hippocampus and pyramidal cell dysregulation of calcium homeostasis and synaptic activity, with a particular focus on early forms of correlated network activity, i.e., giant depolarizing potentials (GDPs), crucially involved in shaping mature synaptic networks. We performed live calcium 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 genetic 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 propose that hyperbilirubinemia damages neurons and affects the refinement of GABAergic synaptic circuitry during a critical period of hippocampal development.