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.

Authors

• Erica Y Shen
• Yan Jiang
• Behnam Javidfar
• Bibi Kassim
• Yong-Hwee E Loh
• Qi Ma
• Amanda C Mitchell
• Venu Pothula
• A Francis Stewart
• Patricia Ernst
• Wei-Dong Yao
• Gilles Martin
• Li Shen
• Mira Jakovcevski
• Schahram Akbarian

Publication/Presentation Date

12-1-2016

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.

Volume

41

Issue

13

First Page

3103

Last Page

3113

ISSN

1740-634X

Published In/Presented At

Shen, E. Y., Jiang, Y., Javidfar, B., Kassim, B., Loh, Y. E., Ma, Q., Mitchell, A. C., Pothula, V., Stewart, A. F., Ernst, P., Yao, W. D., Martin, G., Shen, L., Jakovcevski, M., & Akbarian, S. (2016). 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. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41(13), 3103–3113. https://doi.org/10.1038/npp.2016.144

Disciplines

Medicine and Health Sciences

PubMedID

27485686

Department(s)

Medical Education

Document Type

Article