title: Unconjugated bilirubin exposure impairs hippocampal long-term synaptic plasticity.
abstract: BACKGROUND
  Jaundice is one of the most common problems encountered in newborn infants, due to immaturity of hepatic conjugation and transport processes for bilirubin. Although the majority of neonatal jaundice is benign, some neonates with severe hyperbilirubinemia develop bilirubin encephalopathy or kernicterus. Accumulation of unconjugated bilirubin (UCB) in selected brain regions may result in temporary or permanent impairments of auditory, motor, or cognitive function; however, the molecular mechanisms by which UCB elicits such neurotoxicity are still poorly understood. The present study is undertaken to investigate whether prolonged exposure of rat organotypic hippocampal slice cultures to UCB alters the induction of long-term synaptic plasticity.
  
  
  RESULTS
  Using electrophysiological recording techniques, we find that exposure of hippocampal slice cultures to clinically relevant concentrations of UCB for 24 or 48 h results in an impairment of CA1 long-term potentiation (LTP) and long-term depression (LTD) induction in a time- and concentration-dependent manner. Hippocampal slice cultures stimulated with UCB show no changes in the secretion profiles of the pro-inflammatory cytokines, interleukin-1beta and tumor necrosis factor-alpha, or the propidium ioide uptake. UCB treatment produced a significant decrease in the levels of NR1, NR2A and NR2B subunits of N-methyl-D-aspartate (NMDA) receptors through a calpain-mediated proteolytic cleavage mechanism. Pretreatment of the hippocampal slice cultures with NMDA receptor antagonist or calpain inhibitors effectively prevented the UCB-induced impairment of LTP and LTD.
  
  
  CONCLUSIONS
  Our results indicate that the proteolytic cleavage of NMDA receptor subunits by calpain may play a critical role in mediating the UCB-induced impairment of long-term synaptic plasticity in the hippocampus. These observations provide new insights into the molecular mechanisms underlying UCB-induced impairment of hippocampal synaptic plasticity which, in turn, might provide opportunities for the development of novel therapeutic strategies that targets these pathways for treatment.
authors.affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Fang-Yu
authors.initials: FY
authors.lastname: Chang
authors.forename: Cheng-Che
authors.initials: CC
authors.lastname: Lee
authors.forename: Chiung-Chun
authors.initials: CC
authors.lastname: Huang
authors.forename: Kuei-Sen
authors.initials: KS
authors.lastname: Hsu
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000494:pharmacology*; D002154:Calpain / Q000378:metabolism; D004594:Electrophysiology / Q000379:methods; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007565:Jaundice / Q000175:diagnosis / Q000503:physiopathology*; D017774:Long-Term Potentiation; D036881:Long-Term Synaptic Depression; D008297:Male; D009473:Neuronal Plasticity; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D016194:Receptors, N-Methyl-D-Aspartate; D002154:Calpain; D001663:Bilirubin