Knockdown of the aryl hydrocarbon receptor attenuates excitotoxicity and enhances NMDA-induced BDNF expression in cortical neurons

Chun Hua Lin, Chien Chang Chen, Chih Ming Chou, Chen Yu Wang, Chia Chi Hung, Julia Y. Chen, Heng Wei Chang, Yung Chuan Chen, Gean Chan Yeh, Yi-Hsuan Lee

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

NMDA receptors play dual and opposing roles in neuronal survival by mediating the activity-dependent neurotrophic signaling and excitotoxic cell death via synaptic and extrasynaptic receptors, respectively. In this study, we demonstrate that the aryl hydrocarbon receptor (AhR), also known as the dioxin receptor, is involved in the expression and the opposing activities of NMDA receptors. In primary cultured cortical neurons, we found that NMDA excitotoxicity is significantly enhanced by an AhR agonist 2,3,7,8- tetrachlorodibenzo-p-dioxin, and AhR knockdown with small interfering RNA significantly reduces NMDA excitotoxicity. AhR knockdown also significantly reduces NMDA-increases intracellular calcium concentration, NMDA receptor expression and surface presentation, and moderately decreases the NMDA receptor-mediated spontaneous as well as miniature excitatory post-synaptic currents. However, AhR knockdown significantly enhances the bath NMDA application- but not synaptic NMDA receptor-induced brain-derived neurotrophic factor (BDNF) gene expression, and activating AhR reduces the bath NMDA-induced BDNF expression. Furthermore, AhR knockdown reveals the calcium dependency of NMDA-induced BDNF expression and the binding activity of cAMP-responsive element binding protein (CREB) and its calcium-dependent coactivator CREB binding protein (CBP) to the BDNF promoter upon NMDA treatment. Together, our results suggest that AhR opposingly regulates NMDA receptor-mediated excitotoxicity and neurotrophism possibly by differentially regulating the expression of synaptic and extrasynaptic NMDA receptors.

Original languageEnglish
Pages (from-to)777-789
Number of pages13
JournalJournal of Neurochemistry
Volume111
Issue number3
DOIs
Publication statusPublished - Nov 2009

Fingerprint

Aryl Hydrocarbon Receptors
Brain-Derived Neurotrophic Factor
N-Methylaspartate
Neurons
N-Methyl-D-Aspartate Receptors
Neurotransmitter Receptor
Baths
Carrier Proteins
Calcium
Calcium-Binding Proteins
Cell death
Protein Binding
Gene expression
Small Interfering RNA
Cell Death
Gene Expression

Keywords

  • Aryl hydrocarbon receptor
  • Brain-derived neurotrophic factor
  • CAMP-responsive element binding protein
  • Excitotoxicity
  • NMDA receptor

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Knockdown of the aryl hydrocarbon receptor attenuates excitotoxicity and enhances NMDA-induced BDNF expression in cortical neurons. / Lin, Chun Hua; Chen, Chien Chang; Chou, Chih Ming; Wang, Chen Yu; Hung, Chia Chi; Chen, Julia Y.; Chang, Heng Wei; Chen, Yung Chuan; Yeh, Gean Chan; Lee, Yi-Hsuan.

In: Journal of Neurochemistry, Vol. 111, No. 3, 11.2009, p. 777-789.

Research output: Contribution to journalArticle

Lin, Chun Hua ; Chen, Chien Chang ; Chou, Chih Ming ; Wang, Chen Yu ; Hung, Chia Chi ; Chen, Julia Y. ; Chang, Heng Wei ; Chen, Yung Chuan ; Yeh, Gean Chan ; Lee, Yi-Hsuan. / Knockdown of the aryl hydrocarbon receptor attenuates excitotoxicity and enhances NMDA-induced BDNF expression in cortical neurons. In: Journal of Neurochemistry. 2009 ; Vol. 111, No. 3. pp. 777-789.
@article{ac5a2f4526ac475b967e6ab65f4455f4,
title = "Knockdown of the aryl hydrocarbon receptor attenuates excitotoxicity and enhances NMDA-induced BDNF expression in cortical neurons",
abstract = "NMDA receptors play dual and opposing roles in neuronal survival by mediating the activity-dependent neurotrophic signaling and excitotoxic cell death via synaptic and extrasynaptic receptors, respectively. In this study, we demonstrate that the aryl hydrocarbon receptor (AhR), also known as the dioxin receptor, is involved in the expression and the opposing activities of NMDA receptors. In primary cultured cortical neurons, we found that NMDA excitotoxicity is significantly enhanced by an AhR agonist 2,3,7,8- tetrachlorodibenzo-p-dioxin, and AhR knockdown with small interfering RNA significantly reduces NMDA excitotoxicity. AhR knockdown also significantly reduces NMDA-increases intracellular calcium concentration, NMDA receptor expression and surface presentation, and moderately decreases the NMDA receptor-mediated spontaneous as well as miniature excitatory post-synaptic currents. However, AhR knockdown significantly enhances the bath NMDA application- but not synaptic NMDA receptor-induced brain-derived neurotrophic factor (BDNF) gene expression, and activating AhR reduces the bath NMDA-induced BDNF expression. Furthermore, AhR knockdown reveals the calcium dependency of NMDA-induced BDNF expression and the binding activity of cAMP-responsive element binding protein (CREB) and its calcium-dependent coactivator CREB binding protein (CBP) to the BDNF promoter upon NMDA treatment. Together, our results suggest that AhR opposingly regulates NMDA receptor-mediated excitotoxicity and neurotrophism possibly by differentially regulating the expression of synaptic and extrasynaptic NMDA receptors.",
keywords = "Aryl hydrocarbon receptor, Brain-derived neurotrophic factor, CAMP-responsive element binding protein, Excitotoxicity, NMDA receptor",
author = "Lin, {Chun Hua} and Chen, {Chien Chang} and Chou, {Chih Ming} and Wang, {Chen Yu} and Hung, {Chia Chi} and Chen, {Julia Y.} and Chang, {Heng Wei} and Chen, {Yung Chuan} and Yeh, {Gean Chan} and Yi-Hsuan Lee",
year = "2009",
month = "11",
doi = "10.1111/j.1471-4159.2009.06364.x",
language = "English",
volume = "111",
pages = "777--789",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Knockdown of the aryl hydrocarbon receptor attenuates excitotoxicity and enhances NMDA-induced BDNF expression in cortical neurons

AU - Lin, Chun Hua

AU - Chen, Chien Chang

AU - Chou, Chih Ming

AU - Wang, Chen Yu

AU - Hung, Chia Chi

AU - Chen, Julia Y.

AU - Chang, Heng Wei

AU - Chen, Yung Chuan

AU - Yeh, Gean Chan

AU - Lee, Yi-Hsuan

PY - 2009/11

Y1 - 2009/11

N2 - NMDA receptors play dual and opposing roles in neuronal survival by mediating the activity-dependent neurotrophic signaling and excitotoxic cell death via synaptic and extrasynaptic receptors, respectively. In this study, we demonstrate that the aryl hydrocarbon receptor (AhR), also known as the dioxin receptor, is involved in the expression and the opposing activities of NMDA receptors. In primary cultured cortical neurons, we found that NMDA excitotoxicity is significantly enhanced by an AhR agonist 2,3,7,8- tetrachlorodibenzo-p-dioxin, and AhR knockdown with small interfering RNA significantly reduces NMDA excitotoxicity. AhR knockdown also significantly reduces NMDA-increases intracellular calcium concentration, NMDA receptor expression and surface presentation, and moderately decreases the NMDA receptor-mediated spontaneous as well as miniature excitatory post-synaptic currents. However, AhR knockdown significantly enhances the bath NMDA application- but not synaptic NMDA receptor-induced brain-derived neurotrophic factor (BDNF) gene expression, and activating AhR reduces the bath NMDA-induced BDNF expression. Furthermore, AhR knockdown reveals the calcium dependency of NMDA-induced BDNF expression and the binding activity of cAMP-responsive element binding protein (CREB) and its calcium-dependent coactivator CREB binding protein (CBP) to the BDNF promoter upon NMDA treatment. Together, our results suggest that AhR opposingly regulates NMDA receptor-mediated excitotoxicity and neurotrophism possibly by differentially regulating the expression of synaptic and extrasynaptic NMDA receptors.

AB - NMDA receptors play dual and opposing roles in neuronal survival by mediating the activity-dependent neurotrophic signaling and excitotoxic cell death via synaptic and extrasynaptic receptors, respectively. In this study, we demonstrate that the aryl hydrocarbon receptor (AhR), also known as the dioxin receptor, is involved in the expression and the opposing activities of NMDA receptors. In primary cultured cortical neurons, we found that NMDA excitotoxicity is significantly enhanced by an AhR agonist 2,3,7,8- tetrachlorodibenzo-p-dioxin, and AhR knockdown with small interfering RNA significantly reduces NMDA excitotoxicity. AhR knockdown also significantly reduces NMDA-increases intracellular calcium concentration, NMDA receptor expression and surface presentation, and moderately decreases the NMDA receptor-mediated spontaneous as well as miniature excitatory post-synaptic currents. However, AhR knockdown significantly enhances the bath NMDA application- but not synaptic NMDA receptor-induced brain-derived neurotrophic factor (BDNF) gene expression, and activating AhR reduces the bath NMDA-induced BDNF expression. Furthermore, AhR knockdown reveals the calcium dependency of NMDA-induced BDNF expression and the binding activity of cAMP-responsive element binding protein (CREB) and its calcium-dependent coactivator CREB binding protein (CBP) to the BDNF promoter upon NMDA treatment. Together, our results suggest that AhR opposingly regulates NMDA receptor-mediated excitotoxicity and neurotrophism possibly by differentially regulating the expression of synaptic and extrasynaptic NMDA receptors.

KW - Aryl hydrocarbon receptor

KW - Brain-derived neurotrophic factor

KW - CAMP-responsive element binding protein

KW - Excitotoxicity

KW - NMDA receptor

UR - http://www.scopus.com/inward/record.url?scp=70349900389&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70349900389&partnerID=8YFLogxK

U2 - 10.1111/j.1471-4159.2009.06364.x

DO - 10.1111/j.1471-4159.2009.06364.x

M3 - Article

C2 - 19712055

AN - SCOPUS:70349900389

VL - 111

SP - 777

EP - 789

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 3

ER -