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

Autor: Gong LN; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China., Liu HW; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China., Lai K; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.; Programs in Neurosciences & Mental Health, SickKids Research Institute and Department of Physiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada., Zhang Z; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China., Mao LF; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China., Liu ZQ; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.; Programs in Neurosciences & Mental Health, SickKids Research Institute and Department of Physiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada., Li MX; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.; Department of Head & Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, China., Yin XL; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.; Department of Head & Neck Surgery, Renji Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China., Liang M; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China.; Department of Otorhinolaryngology Head & Neck Surgery, Xinhua Hospital and Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China., Shi HB; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China hbshi@sjtu.edu.cn luyang.wang@utoronto.ca skyin@sjtu.edu.cn., Wang LY; Programs in Neurosciences & Mental Health, SickKids Research Institute and Department of Physiology, University of Toronto, Toronto, Ontario M5G 1X8, Canada hbshi@sjtu.edu.cn luyang.wang@utoronto.ca skyin@sjtu.edu.cn., Yin SK; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China hbshi@sjtu.edu.cn luyang.wang@utoronto.ca skyin@sjtu.edu.cn.
Jazyk: angličtina
Zdroj: The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2024 Nov 06; Vol. 44 (45). Date of Electronic Publication: 2024 Nov 06.
DOI: 10.1523/JNEUROSCI.0442-24.2024
Abstrakt: Hyperbilirubinemia (HB) is a key risk factor for hearing loss in neonates, particularly premature infants. Here, we report that bilirubin (BIL)-dependent cell death in the auditory brainstem of neonatal mice of both sexes is significantly attenuated by ZD7288, a blocker for hyperpolarization-activated cyclic nucleotide-gated (HCN) channel-mediated current ( I h ), or by genetic deletion of HCN1. GABAergic inhibitory interneurons predominantly express HCN1, on which BIL selectively acts to increase their intrinsic excitability and mortality by enhancing HCN1 activity and Ca 2+ -dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, I h , and death, compromising audition at the young adult stage in HCN1 +/+ , but not in HCN1 -/- genotype. We conclude that HB preferentially targets HCN1 to injure inhibitory interneurons, fueling a feedforward loop in which lessening inhibition cascades hyperexcitability, Ca 2+ overload, neuronal death, and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.
Competing Interests: The authors declare no competing financial interests.
(Copyright © 2024 the authors.)
Databáze: MEDLINE
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