MeCP2 and histone deacetylases 1 and 2 in dorsal striatum collectively suppress repetitive behaviors.
Class I histone deacetylases (HDACs) Hdac1 and Hdac2 can associate together in protein complexes with transcriptional factors such as methyl-CpG-binding protein 2 (MeCP2). Given their high degree of sequence identity, we examined whether Hdac1 and Hdac2 were functionally redundant in mature mouse brain. We demonstrate that postnatal forebrain-specific deletion of both Hdac1 and Hdac2 in mice impacts neuronal survival and results in an excessive grooming phenotype caused by dysregulation of Sap90/Psd95-associated protein 3 (Sapap3; also known as Dlgap3) in striatum. Moreover, Hdac1- and Hdac2-dependent regulation of Sapap3 expression requires MECP2, the gene involved in the pathophysiology of Rett syndrome. We show that postnatal forebrain-specific deletion of Mecp2 causes excessive grooming, which is rescued by restoring striatal Sapap3 expression. Our results provide new insight into the upstream regulation of Sapap3 and establish the essential role of striatal Hdac1, Hdac2 and MeCP2 for suppression of repetitive behaviors.
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Melissa
M
Mahgoub
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Megumi
M
Adachi
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Kanzo
K
Suzuki
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Xihui
X
Liu
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Ege T
ET
Kavalali
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.|Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Maria H
MH
Chahrour
Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Lisa M
LM
Monteggia
D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002490:Central Nervous System / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D056284:Histone Deacetylase 1 / Q000235:genetics*; D056464:Histone Deacetylase 2 / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D015518:Rett Syndrome / Q000235:genetics*
C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; C523020:Sapap3 protein, mouse; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2
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