Selective Vulnerability of GABAergic Inhibitory Interneurons to Bilirubin Neurotoxicity in the Neonatal Brain

Area of Science:

• Neuroscience
• Ophthalmology
• Genetics

Background:

• Hyperbilirubinemia (HB) is a significant risk factor for neonatal hearing loss, especially in premature infants.
• Bilirubin (BIL) toxicity affects the auditory brainstem, leading to neuronal damage and hearing deficits.

Purpose of the Study:

• To investigate the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, specifically HCN1, in bilirubin-induced auditory brainstem injury.
• To explore the therapeutic potential of targeting HCN1 channels for preventing hearing loss associated with neonatal hyperbilirubinemia.

Main Methods:

• Utilized neonatal mouse models with induced hyperbilirubinemia.
• Administered ZD7288, an HCN channel blocker, or employed genetic deletion of HCN1.
• Assessed neuronal excitability, cell death, and auditory function in young adults.

Main Results:

• Bilirubin-induced cell death in the auditory brainstem was significantly reduced by ZD7288 or HCN1 deletion.
• HCN1 channels in GABAergic inhibitory interneurons were selectively targeted by bilirubin, increasing excitability and mortality.
• Neonatal hyperbilirubinemia led to increased spontaneous interneuron activity, firing frequency, and neuronal death, compromising audition in HCN1+/+ mice but not in HCN1-/- mice.

Conclusions:

• Hyperbilirubinemia preferentially injures inhibitory interneurons by targeting HCN1 channels, creating a feedforward loop of hyperexcitability and neuronal death.
• HCN1 channel activity is crucial for bilirubin-induced auditory neurotoxicity.
• Targeting HCN1 channels represents a promising strategy for managing hyperbilirubinemia encephalopathy and preventing associated hearing impairments.