title: Opposing role for Egr3 in nucleus accumbens cell subtypes in cocaine action.
abstract: An imbalance in molecular signaling cascades and transcriptional regulation in nucleus accumbens (NAc) medium spiny neuron (MSN) subtypes, those enriched in dopamine D1 versus D2 receptors, is implicated in the behavioral responses to psychostimulants. To provide further insight into the molecular mechanisms occurring in MSN subtypes by cocaine, we examined the transcription factor early growth response 3 (Egr3). We evaluated Egr3 because it is a target of critical cocaine-mediated signaling pathways and because Egr3-binding sites are found on promoters of key cocaine-associated molecules. We first used a RiboTag approach to obtain ribosome-associated transcriptomes from each MSN subtype and found that repeated cocaine administration induced Egr3 ribosome-associated mRNA in NAc D1-MSNs while reducing Egr3 in D2-MSNs. Using Cre-inducible adeno-associated viruses combined with D1-Cre and D2-Cre mouse lines, we observed that Egr3 overexpression in D1-MSNs enhances rewarding and locomotor responses to cocaine, whereas overexpression in D2-MSNs blunts these behaviors. miRNA knock-down of Egr3 in MSN subtypes produced opposite behavioral responses from those observed with overexpression. Finally, we found that repeated cocaine administration altered Egr3 binding to promoters of genes that are important for cocaine-mediated cellular and behavioral plasticity. Genes with increased Egr3 binding to promoters, Camk2α, CREB, FosB, Nr4a2, and Sirt1, displayed increased mRNA in D1-MSNs and, in some cases, a reduction in D2-MSNs. Histone and the DNA methylation enzymes G9a and Dnmt3a displayed reduced Egr3 binding to their promoters and reduced mRNA in D1-MSNs. Our study provides novel insight into an opposing role of Egr3 in select NAc MSN subtypes in cocaine action.
authors.affiliation: Department of Anatomy and Neurobiology and.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Chandra
authors.affiliation: Department of Anatomy and Neurobiology and.
authors.forename: T Chase
authors.initials: TC
authors.lastname: Francis
authors.affiliation: Department of Medicine, Division of Nephrology, University of Maryland School of Medicine Baltimore, Maryland 21201, and.
authors.forename: Prasad
authors.initials: P
authors.lastname: Konkalmatt
authors.affiliation: Department of Anatomy and Neurobiology and.
authors.forename: Ariunzaya
authors.initials: A
authors.lastname: Amgalan
authors.affiliation: Department of Pharmacology and Toxicology, The Research Institution Addictions, State University of New York at Buffalo, Buffalo, New York 14214.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Gancarz
authors.affiliation: Department of Pharmacology and Toxicology, The Research Institution Addictions, State University of New York at Buffalo, Buffalo, New York 14214.
authors.forename: David M
authors.initials: DM
authors.lastname: Dietz
authors.affiliation: Department of Anatomy and Neurobiology and mklobo@som.umaryland.edu.
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Lobo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D051776:Early Growth Response Protein 3 / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009474:Neurons / Q000145:classification / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism*; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; C000715535:Dnmt3a protein, mouse; C497369:Egr3 protein, mouse; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D016760:Proto-Oncogene Proteins c-fos; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D051776:Early Growth Response Protein 3; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517671:Camk2a protein, mouse; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: Egr3; RiboTag; cocaine; medium spiny neurons; nucleus accumbens; transcription