Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.
Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli.
LaPlant
Quincey
Q
Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, New York, USA.
Vialou
Vincent
V
Covington
Herbert E
HE
Dumitriu
Dani
D
Feng
Jian
J
Warren
Brandon L
BL
Maze
Ian
I
Dietz
David M
DM
Watts
Emily L
EL
Iñiguez
Sergio D
SD
Koo
Ja Wook
JW
Mouzon
Ezekiell
E
Renthal
William
W
Hollis
Fiona
F
Wang
Hui
H
Noonan
Michele A
MA
Ren
Yanhua
Y
Eisch
Amelia J
AJ
Bolaños
Carlos A
CA
Kabbaj
Mohamed
M
Xiao
Guanghua
G
Neve
Rachael L
RL
Hurd
Yasmin L
YL
Oosting
Ronald S
RS
Fan
Gouping
G
Morrison
John H
JH
Nestler
Eric J
EJ
D000818:Animals; D002908:Chronic Disease; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology*; D003863:Depression / Q000235:genetics / Q000378:metabolism; D004291:Dominance-Subordination; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004644:Emotions / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism
C000715535:Dnmt3a protein, mouse; D018765:Dopamine Uptake Inhibitors; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D003042:Cocaine