MeCP2 in the nucleus accumbens contributes to neural and behavioral responses to psychostimulants.
MeCP2 is a methyl DNA-binding transcriptional regulator that contributes to the development and function of CNS synapses; however, the requirement for MeCP2 in stimulus-regulated behavioral plasticity is not fully understood. Here we show that acute viral manipulation of MeCP2 expression in the nucleus accumbens (NAc) bidirectionally modulates amphetamine (AMPH)-induced conditioned place preference. Mecp2 hypomorphic mutant mice have more NAc GABAergic synapses and show deficient AMPH-induced structural plasticity of NAc dendritic spines. Furthermore, these mice show deficient plasticity of striatal immediate early gene inducibility after repeated AMPH administration. Notably, psychostimulants induce phosphorylation of MeCP2 at Ser421, a site that regulates MeCP2's function as a repressor. Phosphorylation is selectively induced in GABAergic interneurons of the NAc, and its extent strongly predicts the degree of behavioral sensitization. These data reveal new roles for MeCP2 both in mesolimbocortical circuit development and in the regulation of psychostimulant-induced behaviors.
Deng
Jie V
JV
Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA.
Rodriguiz
Ramona M
RM
Hutchinson
Ashley N
AN
Kim
Il-Hwan
IH
Wetsel
William C
WC
West
Anne E
AE
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology; D004327:Drinking Behavior / Q000187:drug effects / Q000502:physiology; D017781:Genes, Immediate-Early / Q000187:drug effects; D007395:Interneurons / Q000187:drug effects / Q000502:physiology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000697:Central Nervous System Stimulants; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D005680:gamma-Aminobutyric Acid; D000661:Amphetamine