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Selective Vulnerability of GABAergic Inhibitory Interneurons to Bilirubin Neurotoxicity in the Neonatal Brain.
Gong, Li-Na; Liu, Han-Wei; Lai, Ke; Zhang, Zhen; Mao, Lin-Fei; Liu, Zhen-Qi; Li, Ming-Xian; Yin, Xin-Lu; Liang, Min; Shi, Hai-Bo; Wang, Lu-Yang; Yin, Shan-Kai.
Afiliación
  • Gong LN; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medical, Shanghai 200233, China.
  • Liu HW; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medical, Shanghai 200233, China.
  • Lai K; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medical, Shanghai 200233, China.
  • Zhang Z; Programs in Neurosciences & Mental Health, SickKids Research Institute and Department of Physiology, University of Toronto, Toronto, ON, M5G 1X8, Canada.
  • Mao LF; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medical, Shanghai 200233, China.
  • Liu ZQ; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medical, Shanghai 200233, China.
  • Li MX; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medical, Shanghai 200233, China.
  • Yin XL; Programs in Neurosciences & Mental Health, SickKids Research Institute and Department of Physiology, University of Toronto, Toronto, ON, M5G 1X8, Canada.
  • Liang M; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medical, Shanghai 200233, China.
  • Shi HB; Department of Head & Neck Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, China.
  • Wang LY; Department of Otorhinolaryngology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medical, Shanghai 200233, China.
  • Yin SK; Department of Head & Neck Surgery, Renji Hospital, School of Medicine and Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
J Neurosci ; 2024 Sep 23.
Article en En | MEDLINE | ID: mdl-39313321
ABSTRACT
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 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 (Ih), 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 Ca2+-dependent membrane targeting. Chronic BIL elevation in neonatal mice in vivo increases the fraction of spontaneously active interneurons and their firing frequency, Ih and death, compromising audition at 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, Ca2+ overload, neuronal death and auditory impairments. These findings rationalize HCN1 as a potential target for managing HB encephalopathy.Significance Statement This study demonstrated that bilirubin preferentially targets GABAergic interneurons where it facilitates not only gating of HCN1 channels but also targeting of intracellular HCN1 to plasma membrane in calcium-dependent manner, resulting in neuronal hyperexcitability, injury and sensory dysfunction. These findings implicate HCN1 channel not only as a potential driver for auditory abnormalities in neonatal patients with bilirubin encephalopathy, but also potential intervention target for clinical management of neurological impairments associated with severe jaundice. Selective vulnerability of interneurons to neurotoxicity may be of general significance for understanding other forms of brain injury.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Neurosci Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: J Neurosci Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos