Dopamine D2-like antagonists induce chromatin remodeling in striatal neurons through cyclic AMP-protein kinase A and NMDA receptor signaling.
Antipsychotic drugs regulate gene transcription in striatal neurons by blocking dopamine D2-like receptors. Little is known about the underlying changes in chromatin structure, including covalent modifications at histone N-terminal tails that are epigenetic regulators of gene expression. We show that treatment with D2-like antagonists rapidly induces the phosphorylation of histone H3 at serine 10 and the acetylation of H3-lysine 14 in bulk chromatin from striatum and in nuclei of striatal neurons. We find that, in vivo, D2-like antagonist-induced H3 phospho-acetylation is inhibited by the NMDA receptor antagonist MK-801 and by the protein kinase A (PKA) inhibitor Rp-adenosine 3c',5c'-cyclic monophosphorothioate triethylammonium salt but increased by the PKA activator Sp-adenosine 3c',5c'-cyclic monophosphorothioate triethylammonium salt. Furthermore, in dissociated striatal cultures which lack midbrain and cortical pre-synaptic inputs, H3 phospho-acetylation was induced by glutamate, L-type Ca2+ channel agonists and activators of cAMP-dependent PKA but inhibited by NMDA receptor antagonists or PKA antagonists. The dual modification, H3pS10-acK14, was enriched at genomic sites with active transcription and showed the kinetics of the early response. Together, these results suggest that histone modifications and chromatin structure in striatal neurons are dynamically regulated by dopaminergic and glutamatergic inputs converging on the cellular level. Blockade of D2-like receptors induces H3 phospho-acetylation, H3pS10-acK14, through cAMP-dependent PKA, and post-synaptic NMDA receptor signaling.
Department of Psychiatry, Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01604, USA.
Jianhong
J
Li
Yin
Y
Guo
Frederick A
FA
Schroeder
Rachael M
RM
Youngs
Thomas W
TW
Schmidt
Craig
C
Ferris
Christine
C
Konradi
Schahram
S
Akbarian
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D015139:Blotting, Southern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D015259:Dopamine Agents / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D004333:Drug Administration Routes; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D016762:Genes, fos / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D007211:Indoles; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D008745:Methylation / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013449:Sulfonamides; D013873:Thionucleotides / Q000494:pharmacology; D013997:Time Factors
D015259:Dopamine Agents; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005904:Glial Fibrillary Acidic Protein; D006657:Histones; D007211:Indoles; D007546:Isoquinolines; D012333:RNA, Messenger; D018091:Receptors, AMPA; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D013449:Sulfonamides; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D018698:Glutamic Acid; C007293:DAPI; D016291:Dizocilpine Maleate; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D010751:Phosphopyruvate Hydratase; D006220:Haloperidol; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C104722:glutamate receptor ionotropic, AMPA 2