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Targeting histone deacetylation for recovery of maternal deprivation-induced changes in BDNF and AKAP150 expression in the VTA.
Shepard, Ryan D; Gouty, Shawn; Kassis, Haifa; Berenji, Aylar; Zhu, William; Cox, Brian M; Nugent, Fereshteh S.
Afiliación
  • Shepard RD; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, MD 20814, USA.
  • Gouty S; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, MD 20814, USA.
  • Kassis H; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, MD 20814, USA.
  • Berenji A; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, MD 20814, USA.
  • Zhu W; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, MD 20814, USA.
  • Cox BM; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, MD 20814, USA.
  • Nugent FS; Uniformed Services University of the Health Sciences, Department of Pharmacology, Bethesda, MD 20814, USA. Electronic address: fereshteh.nugent@usuhs.edu.
Exp Neurol ; 309: 160-168, 2018 11.
Article en En | MEDLINE | ID: mdl-30102916
Severe early life stressors increase the probability of developing psychiatric disorders later in life through modifications in neuronal circuits controlling brain monoaminergic signaling. Our previous work demonstrated that 24 h maternal deprivation (MD) in male Sprague Dawley rats modifies dopamine (DA) signaling from the ventral tegmental area (VTA) through changes at GABAergic synapses that were reversible by in vitro histone deacetylase (HDAC) inhibition which led to restoration of the scaffold A-kinase anchoring protein (AKAP150) signaling and subsequently recovered GABAergic plasticity (Authement et al., 2015). Using a combination of in situ hybridization, Western blots and immunohistochemistry, we confirmed that MD-induced epigenetic modifications at the level of histone acetylation were associated with an upregulation of HDAC2. MD also increased Akap5 mRNA levels in the VTA. Western blot analysis of AKAP150 protein expression showed an increase in synaptic levels of AKAP150 protein in the VTA with an accompanying decrease in synaptic levels of protein kinase A (PKA). Moreover, the abundance of mature brain-derived neurotrophic factor (BDNF) protein of VTA tissues from MD rats was significantly lower than in control groups. In vivo systemic injection with a selective class I HDAC inhibitor (CI-994) was sufficient to reverse MD-induced histone hypoacetylation in the VTA for 24 h after the injection. Furthermore, HDAC inhibition normalized the levels of mBDNF and AKAP150 proteins at 24 h. Our data suggest that HDAC-mediated targeting of BDNF and AKAP-dependent local signaling within VTA could provide novel therapeutics for prevention of later-life psychopathology.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Histonas / Regulación de la Expresión Génica / Área Tegmental Ventral / Factor Neurotrófico Derivado del Encéfalo / Proteínas de Anclaje a la Quinasa A / Privación Materna Límite: Animals Idioma: En Revista: Exp Neurol Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Histonas / Regulación de la Expresión Génica / Área Tegmental Ventral / Factor Neurotrófico Derivado del Encéfalo / Proteínas de Anclaje a la Quinasa A / Privación Materna Límite: Animals Idioma: En Revista: Exp Neurol Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos