title: Selective role for DNMT3a in learning and memory.
abstract: Methylation of cytosine nucleotides is governed by DNA methyltransferases (DNMTs) that establish de novo DNA methylation patterns in early embryonic development (e.g., DNMT3a and DNMT3b) or maintain those patterns on hemimethylated DNA in dividing cells (e.g., DNMT1). DNMTs continue to be expressed at high levels in mature neurons, however their impact on neuronal function and behavior are unclear. To address this issue we examined DNMT1 and DNMT3a expression following associative learning. We also generated forebrain specific conditional Dnmt1 or Dnmt3a knockout mice and characterized them in learning and memory paradigms as well as for alterations in long-term potentiation (LTP) and synaptic plasticity. Here, we report that experience in an associative learning task impacts expression of Dnmt3a, but not Dnmt1, in brain areas that mediate learning of this task. We also found that Dnmt3a knockout mice, and not Dnmt1 knockouts have synaptic alterations as well as learning deficits on several associative and episodic memory tasks. These findings indicate that the de novo DNA methylating enzyme DNMT3a in postmitotic neurons is necessary for normal memory formation and its function cannot be substituted by the maintenance DNA methylating enzyme DNMT1.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, United States; Department of Natural Sciences, University of Michigan - Dearborn, Dearborn, MI 48128, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Morris
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, United States.
authors.forename: Megumi
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, United States.
authors.forename: Elisa S
authors.initials: ES
authors.lastname: Na
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, United States. Electronic address: Lisa.monteggia@utsouthwestern.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Monteggia
mesh_terms: D000818:Animals; D003214:Conditioning, Classical / Q000502:physiology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D000090205:DNA Methyltransferase 3A; D006624:Hippocampus / Q000502:physiology; D007858:Learning / Q000502:physiology*; D017774:Long-Term Potentiation / Q000502:physiology; D008568:Memory / Q000502:physiology*; D061212:Memory, Episodic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000502:physiology
chemical_list: C485852:Dmap1 protein, mouse; C000715535:Dnmt3a protein, mouse; D012097:Repressor Proteins; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: Behavior; Excitatory neurotransmission; Fear conditioning; Long term potentiation; Methylation