Ethanol exposure induces neonatal neurodegeneration by enhancing CB1R Exon1 Histone H4K8 acetylation and up-regulating CB1R function causing neurobehavioral abnormalities in adult mice

Shivakumar Subbanna, Nagaraja N. Nagre, Nagavedi S. Umapathy, Betty S. Pace, Balapal S. Basavarajappa

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Abstract

Background: Ethanol exposure to rodents during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces long-term potentiation and memory deficits. However, the molecular mechanisms underlying these deficits are still poorly understood. Methods: In the present study, we explored the potential role of epigenetic changes at cannabinoid type 1 (CB1R) exon1 and additional CB1R functions, which could promote memory deficits in animal models of fetal alcohol spectrum disorder. Results: We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively. We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice. The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression. CB1R knockout mice exhibited neither ethanolinduced neurodegeneration nor inhibition of CREB phosphorylation or Arc expression. However, both neonatal and adult mice did exhibit enhanced CREB phosphorylation and Arc protein expression. P7 ethanol-treated adult mice exhibited impaired spatial and social recognition memory, which were prevented by the pharmacological blockade or deletion of CB1Rs at P7. Conclusions: Together, these findings suggest that P7 ethanol treatment induces CB1R expression through epigenetic modification of the CB1R gene, and that the enhanced CB1R function induces pCREB, Arc, spatial, and social memory deficits in adult mice.

Original languageEnglish (US)
Pages (from-to)1-15
Number of pages15
JournalInternational Journal of Neuropsychopharmacology
Volume18
Issue number5
DOIs
StatePublished - Mar 1 2015

Fingerprint

Acetylation
Histones
Ethanol
Cytoskeleton
Memory Disorders
Phosphorylation
Proteins
Epigenomics
CREB-Binding Protein
Fetal Alcohol Spectrum Disorders
Long-Term Memory
Cannabinoids
Long-Term Potentiation
Neocortex
Third Pregnancy Trimester
Response Elements
Knockout Mice
Cyclic AMP
Lysine
Rodentia

Keywords

  • Cannabinoid receptor system
  • Epigenetics
  • FASD
  • Memory loss
  • Synaptic signaling

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

@article{71321238c00a4aeebfdcb0a55470435e,
title = "Ethanol exposure induces neonatal neurodegeneration by enhancing CB1R Exon1 Histone H4K8 acetylation and up-regulating CB1R function causing neurobehavioral abnormalities in adult mice",
abstract = "Background: Ethanol exposure to rodents during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces long-term potentiation and memory deficits. However, the molecular mechanisms underlying these deficits are still poorly understood. Methods: In the present study, we explored the potential role of epigenetic changes at cannabinoid type 1 (CB1R) exon1 and additional CB1R functions, which could promote memory deficits in animal models of fetal alcohol spectrum disorder. Results: We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively. We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice. The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression. CB1R knockout mice exhibited neither ethanolinduced neurodegeneration nor inhibition of CREB phosphorylation or Arc expression. However, both neonatal and adult mice did exhibit enhanced CREB phosphorylation and Arc protein expression. P7 ethanol-treated adult mice exhibited impaired spatial and social recognition memory, which were prevented by the pharmacological blockade or deletion of CB1Rs at P7. Conclusions: Together, these findings suggest that P7 ethanol treatment induces CB1R expression through epigenetic modification of the CB1R gene, and that the enhanced CB1R function induces pCREB, Arc, spatial, and social memory deficits in adult mice.",
keywords = "Cannabinoid receptor system, Epigenetics, FASD, Memory loss, Synaptic signaling",
author = "Shivakumar Subbanna and Nagre, {Nagaraja N.} and Umapathy, {Nagavedi S.} and Pace, {Betty S.} and Basavarajappa, {Balapal S.}",
year = "2015",
month = "3",
day = "1",
doi = "10.1093/ijnp/pyu028",
language = "English (US)",
volume = "18",
pages = "1--15",
journal = "International Journal of Neuropsychopharmacology",
issn = "1461-1457",
publisher = "Cambridge University Press",
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TY - JOUR

T1 - Ethanol exposure induces neonatal neurodegeneration by enhancing CB1R Exon1 Histone H4K8 acetylation and up-regulating CB1R function causing neurobehavioral abnormalities in adult mice

AU - Subbanna, Shivakumar

AU - Nagre, Nagaraja N.

AU - Umapathy, Nagavedi S.

AU - Pace, Betty S.

AU - Basavarajappa, Balapal S.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Background: Ethanol exposure to rodents during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces long-term potentiation and memory deficits. However, the molecular mechanisms underlying these deficits are still poorly understood. Methods: In the present study, we explored the potential role of epigenetic changes at cannabinoid type 1 (CB1R) exon1 and additional CB1R functions, which could promote memory deficits in animal models of fetal alcohol spectrum disorder. Results: We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively. We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice. The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression. CB1R knockout mice exhibited neither ethanolinduced neurodegeneration nor inhibition of CREB phosphorylation or Arc expression. However, both neonatal and adult mice did exhibit enhanced CREB phosphorylation and Arc protein expression. P7 ethanol-treated adult mice exhibited impaired spatial and social recognition memory, which were prevented by the pharmacological blockade or deletion of CB1Rs at P7. Conclusions: Together, these findings suggest that P7 ethanol treatment induces CB1R expression through epigenetic modification of the CB1R gene, and that the enhanced CB1R function induces pCREB, Arc, spatial, and social memory deficits in adult mice.

AB - Background: Ethanol exposure to rodents during postnatal day 7 (P7), which is comparable to the third trimester of human pregnancy, induces long-term potentiation and memory deficits. However, the molecular mechanisms underlying these deficits are still poorly understood. Methods: In the present study, we explored the potential role of epigenetic changes at cannabinoid type 1 (CB1R) exon1 and additional CB1R functions, which could promote memory deficits in animal models of fetal alcohol spectrum disorder. Results: We found that ethanol treatment of P7 mice enhances acetylation of H4 on lysine 8 (H4K8ace) at CB1R exon1, CB1R binding as well as the CB1R agonist-stimulated GTPγS binding in the hippocampus and neocortex, two brain regions that are vulnerable to ethanol at P7 and are important for memory formation and storage, respectively. We also found that ethanol inhibits cyclic adenosine monophosphate response element-binding protein (CREB) phosphorylation and activity-regulated cytoskeleton-associated protein (Arc) expression in neonatal and adult mice. The blockade or genetic deletion of CB1Rs prior to ethanol treatment at P7 rescued CREB phosphorylation and Arc expression. CB1R knockout mice exhibited neither ethanolinduced neurodegeneration nor inhibition of CREB phosphorylation or Arc expression. However, both neonatal and adult mice did exhibit enhanced CREB phosphorylation and Arc protein expression. P7 ethanol-treated adult mice exhibited impaired spatial and social recognition memory, which were prevented by the pharmacological blockade or deletion of CB1Rs at P7. Conclusions: Together, these findings suggest that P7 ethanol treatment induces CB1R expression through epigenetic modification of the CB1R gene, and that the enhanced CB1R function induces pCREB, Arc, spatial, and social memory deficits in adult mice.

KW - Cannabinoid receptor system

KW - Epigenetics

KW - FASD

KW - Memory loss

KW - Synaptic signaling

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U2 - 10.1093/ijnp/pyu028

DO - 10.1093/ijnp/pyu028

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C2 - 25609594

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VL - 18

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JO - International Journal of Neuropsychopharmacology

JF - International Journal of Neuropsychopharmacology

SN - 1461-1457

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