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Unconjugated bilirubin exposure impairs hippocampal long-term synaptic plasticity.

Chang FY, Lee CC, Huang CC, Hsu KS - PLoS ONE (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

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.

Methodology/principal findings: 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.

Conclusion/significance: 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.

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Related in: MedlinePlus

Effects of prolonged UCB exposure on propidium iodide (PI) staining in hippocampal slice cultures.(A) Representative images of PI staining in slices from control or treatment with UCB (1 µM or 10 µM) or kainic acid (60 µM) for 24 or 48 h. (B) Densitometry quantification of PI staining similar to those shown in (A). Data are expressed as fold of increase over the respective control group. Number of experiments is indicated in the parenthesis.
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pone-0005876-g006: Effects of prolonged UCB exposure on propidium iodide (PI) staining in hippocampal slice cultures.(A) Representative images of PI staining in slices from control or treatment with UCB (1 µM or 10 µM) or kainic acid (60 µM) for 24 or 48 h. (B) Densitometry quantification of PI staining similar to those shown in (A). Data are expressed as fold of increase over the respective control group. Number of experiments is indicated in the parenthesis.

Mentions: It has been shown that UCB can reduce glutamate uptake in astrocytes and in turn induces neuronal injury or death [24], [25]. We therefore asked whether the impairment of LTP and LTD induction observed in UCB-treated slices is attributed to UCB-mediated excitotoxicity. With propidium iodide (PI) staining, UCB (1 or 10 µM) treatment for 24 h or 48 h did not result in higher PI uptake than in control slices (Figure 6A and B). In contrast, exposure of slice to kainic acid (60 µM) for 24 or 48 h resulted in a significant increase in the PI staining. These results indicate that the UCB treatment regimen used in the present study did not affect neuronal viability.


Unconjugated bilirubin exposure impairs hippocampal long-term synaptic plasticity.

Chang FY, Lee CC, Huang CC, Hsu KS - PLoS ONE (2009)

Effects of prolonged UCB exposure on propidium iodide (PI) staining in hippocampal slice cultures.(A) Representative images of PI staining in slices from control or treatment with UCB (1 µM or 10 µM) or kainic acid (60 µM) for 24 or 48 h. (B) Densitometry quantification of PI staining similar to those shown in (A). Data are expressed as fold of increase over the respective control group. Number of experiments is indicated in the parenthesis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2690688&req=5

pone-0005876-g006: Effects of prolonged UCB exposure on propidium iodide (PI) staining in hippocampal slice cultures.(A) Representative images of PI staining in slices from control or treatment with UCB (1 µM or 10 µM) or kainic acid (60 µM) for 24 or 48 h. (B) Densitometry quantification of PI staining similar to those shown in (A). Data are expressed as fold of increase over the respective control group. Number of experiments is indicated in the parenthesis.
Mentions: It has been shown that UCB can reduce glutamate uptake in astrocytes and in turn induces neuronal injury or death [24], [25]. We therefore asked whether the impairment of LTP and LTD induction observed in UCB-treated slices is attributed to UCB-mediated excitotoxicity. With propidium iodide (PI) staining, UCB (1 or 10 µM) treatment for 24 h or 48 h did not result in higher PI uptake than in control slices (Figure 6A and B). In contrast, exposure of slice to kainic acid (60 µM) for 24 or 48 h resulted in a significant increase in the PI staining. These results indicate that the UCB treatment regimen used in the present study did not affect neuronal viability.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

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.

Methodology/principal findings: 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.

Conclusion/significance: 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.

Show MeSH
Related in: MedlinePlus