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
Shen, Erica Y.Jiang, Yan
Javidfar, Behnam
Kassim, Bibi
Loh, Yong-Hwee E.
Ma, Qi
Mitchell, Amanda C.
Pothula, Venu
Stewart, A. Francis
Ernst, Patricia
Yao, Wei-Dong
Martin, Gilles E.
Shen, Li
Jakovcevski, Mira
Akbarian, Schahram
UMass Chan Affiliations
Martin LabDepartment of Psychiatry
Brudnick Neuropsychiatric Research Institute
Document Type
Journal ArticlePublication Date
2016-12-01Keywords
Mental and Social HealthMolecular and Cellular Neuroscience
Psychiatry
Psychiatry and Psychology
Metadata
Show full item recordAbstract
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.Source
Neuropsychopharmacology. 2016 Dec;41(13):3103-3113. doi: 10.1038/npp.2016.144. Epub 2016 Aug 3. Link to article on publisher's site
DOI
10.1038/npp.2016.144Permanent Link to this Item
http://hdl.handle.net/20.500.14038/46239PubMed ID
27485686Related Resources
ae974a485f413a2113503eed53cd6c53
10.1038/npp.2016.144