title: G9a influences neuronal subtype specification in striatum.
abstract: Cocaine-mediated repression of the histone methyltransferase (HMT) G9a has recently been implicated in transcriptional, morphological and behavioral responses to chronic cocaine administration. Here, using a ribosomal affinity purification approach, we found that G9a repression by cocaine occurred in both Drd1-expressing (striatonigral) and Drd2-expressing (striatopallidal) medium spiny neurons. Conditional knockout and overexpression of G9a within these distinct cell types, however, revealed divergent behavioral phenotypes in response to repeated cocaine treatment. Our studies further indicated that such developmental deletion of G9a selectively in Drd2 neurons resulted in the unsilencing of transcriptional programs normally specific to striatonigral neurons and in the acquisition of Drd1-associated projection and electrophysiological properties. This partial striatopallidal to striatonigral 'switching' phenotype in mice indicates a new role for G9a in contributing to neuronal subtype identity and suggests a critical function for cell type-specific histone methylation patterns in the regulation of behavioral responses to environmental stimuli.
authors.affiliation: Laboratory of Chromatin Biology and Epigenetics, The Rockefeller University, New York, New York, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Maze
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Dipesh
authors.initials: D
authors.lastname: Chaudhury
authors.affiliation: Department of Pharmacology and Toxicology, University at Buffalo, Buffalo, New York, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Dietz
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Von Schimmelmann
authors.affiliation: Department of Psychology, University of California, Los Angeles, Los Angeles, California, USA.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Kennedy
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Lobo
authors.affiliation: 1] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Daws
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Miller
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Rosemary C
authors.initials: RC
authors.lastname: Bagot
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Haosheng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Depressive Disorders Program, Douglas Mental Health University and McGill University, Montréal, Québec, Canada.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.affiliation: Department of Brain and Cognitive Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Rachael L
authors.initials: RL
authors.lastname: Neve
authors.affiliation: 1] Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [3] Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Yasmin L
authors.initials: YL
authors.lastname: Hurd
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.affiliation: 1] Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Ming-Hu
authors.initials: MH
authors.lastname: Han
authors.affiliation: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Schaefer
authors.affiliation: 1] Department of Pharmacology and Systems Therapeutics, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. [2] Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology* / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000378:metabolism / Q000502:physiology*; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D009928:Organ Specificity; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D003042:Cocaine