title: Neuronal Deletion of Kmt2a/Mll1 Histone Methyltransferase in Ventral Striatum is Associated with Defective Spike-Timing-Dependent Striatal Synaptic Plasticity, Altered Response to Dopaminergic Drugs, and Increased Anxiety.
abstract: Lysine (K) methyltransferase 2a (Kmt2a) and other regulators of H3 lysine 4 methylation, a histone modification enriched at promoters and enhancers, are widely expressed throughout the brain, but molecular and cellular phenotypes in subcortical areas remain poorly explored. We report that Kmt2a conditional deletion in postnatal forebrain is associated with excessive nocturnal activity and with absent or blunted responses to stimulant and dopaminergic agonist drugs, in conjunction with near-complete loss of spike-timing-dependent long-term potentiation in medium spiny neurons (MSNs). Selective ablation of Kmt2a, but not the ortholog Kmt2b, in adult ventral striatum/nucleus accumbens neurons markedly increased anxiety scores in multiple behavioral paradigms. Striatal transcriptome sequencing in adult mutants identified 262 Kmt2a-sensitive genes, mostly downregulated in Kmt2a-deficient mice. Transcriptional repression includes the 5-Htr2a serotonin receptor, strongly associated with anxiety- and depression-related disorders in human and animal models. Consistent with the role of Kmt2a in promoting gene expression, the transcriptional regulators Bahcc1, Isl1, and Sp9 were downregulated and affected by H3K4 promoter hypomethylation. Therefore, Kmt2a regulates synaptic plasticity in striatal neurons and provides an epigenetic drug target for anxiety and dopamine-mediated behaviors.
authors.affiliation: Department of Psychiatry, New York, NY, USA.
authors.forename: Erica Y
authors.initials: EY
authors.lastname: Shen
authors.affiliation: Department of Psychiatry, New York, NY, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Psychiatry, New York, NY, USA.
authors.forename: Behnam
authors.initials: B
authors.lastname: Javidfar
authors.affiliation: Department of Psychiatry, New York, NY, USA.
authors.forename: Bibi
authors.initials: B
authors.lastname: Kassim
authors.affiliation: Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, NY, USA.
authors.forename: Yong-Hwee E
authors.initials: YE
authors.lastname: Loh
authors.affiliation: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Psychiatry, New York, NY, USA.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Mitchell
authors.affiliation: Department of Psychiatry, New York, NY, USA.
authors.forename: Venu
authors.initials: V
authors.lastname: Pothula
authors.affiliation: Biotechnology Center, Technische Universitaet, Dresden, Germany.
authors.forename: A Francis
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: University of Colorado School of Medicine, Department of Pediatrics, Aurora, CO, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ernst
authors.affiliation: Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, NY, USA.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Yao
authors.affiliation: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, MA, USA.
authors.forename: Gilles
authors.initials: G
authors.lastname: Martin
authors.affiliation: Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, Hess Center for Science and Medicine, New York, NY, USA.
authors.forename: Li
authors.identifier: 0000-0002-5190-2851
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Munich, Germany.
authors.forename: Mira
authors.initials: M
authors.lastname: Jakovcevski
authors.affiliation: Department of Psychiatry, New York, NY, USA.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D001007:Anxiety / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D002940:Circadian Rhythm / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000494:pharmacology*; D005260:Female; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency* / Q000235:genetics; D008124:Locomotion / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000172:deficiency* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D066328:Ventral Striatum / Q000166:cytology*
chemical_list: D015259:Dopamine Agents; D009419:Nerve Tissue Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse