Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons.
Dnmt1 and Dnmt3a are important DNA methyltransferases that are expressed in postmitotic neurons, but their function in the CNS is unclear. We generated conditional mutant mice that lack Dnmt1, Dnmt3a or both exclusively in forebrain excitatory neurons and found that only double knockout (DKO) mice showed abnormal long-term plasticity in the hippocampal CA1 region together with deficits in learning and memory. Although we found no neuronal loss, hippocampal neurons in DKO mice were smaller than in the wild type; furthermore, DKO neurons showed deregulated expression of genes, including the class I MHC genes and Stat1, that are known to contribute to synaptic plasticity. In addition, we observed a significant decrease in DNA methylation in DKO neurons. We conclude that Dnmt1 and Dnmt3a are required for synaptic plasticity, learning and memory through their overlapping roles in maintaining DNA methylation and modulating neuronal gene expression in adult CNS neurons.
Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA.
Jian
J
Feng
Yu
Y
Zhou
Susan L
SL
Campbell
Thuc
T
Le
En
E
Li
J David
JD
Sweatt
Alcino J
AJ
Silva
Guoping
G
Fan
D000367:Age Factors; D000818:Animals; D002478:Cells, Cultured; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D005260:Female; D018507:Gene Expression Regulation, Developmental; D007858:Learning / Q000502:physiology; D008297:Male; D008568:Memory / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009473:Neuronal Plasticity / Q000235:genetics; D009474:Neurons / Q000502:physiology*; D016548:Prosencephalon / Q000502:physiology*; D013569:Synapses / Q000235:genetics / Q000502:physiology*
C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C000619381:Dnmt1 protein, mouse