G9a influences neuronal subtype specification in striatum.

TitleG9a influences neuronal subtype specification in striatum.
Publication TypeJournal Article
Year of Publication2014
AuthorsMaze I, Chaudhury D, Dietz DM, Von Schimmelmann M, Kennedy PJ, Lobo MKay, Sillivan SE, Miller ML, Bagot RC, Sun H, Turecki G, Neve RL, Hurd YL, Shen L, Han M-H, Schaefer A, Nestler EJ
JournalNat Neurosci
Volume17
Issue4
Pagination533-9
Date Published2014 Apr
ISSN1546-1726
KeywordsAdolescent, Adult, Aged, Animals, Cocaine, Corpus Striatum, Dopaminergic Neurons, Female, Histone-Lysine N-Methyltransferase, Humans, Male, Mice, Middle Aged, Organ Specificity, Receptors, Dopamine D1, Receptors, Dopamine D2, Young Adult
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.

DOI10.1038/nn.3670
Alternate JournalNat. Neurosci.
PubMed ID24584053
PubMed Central IDPMC3972624
Grant ListDA025962 / DA / NIDA NIH HHS / United States
DP2 MH100012 / MH / NIMH NIH HHS / United States
MH092306 / MH / NIMH NIH HHS / United States
P01 DA008227 / DA / NIDA NIH HHS / United States
P01DA08227 / DA / NIDA NIH HHS / United States
P50 MH096890 / MH / NIMH NIH HHS / United States
P50MH96890 / MH / NIMH NIH HHS / United States
R01 DA007359 / DA / NIDA NIH HHS / United States
R01 MH092306 / MH / NIMH NIH HHS / United States
R37 DA007359 / DA / NIDA NIH HHS / United States

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