title: Histone Deacetylase Inhibition Rescues Maternal Deprivation-Induced GABAergic Metaplasticity through Restoration of AKAP Signaling.
abstract: Adverse early-life experiences such as child neglect and abuse increase the risk of developing addiction and stress-related disorders through alterations in motivational systems including the mesolimbic dopamine (DA) pathway. Here we investigated whether a severe early-life stress (i.e., maternal deprivation, MD) promotes DA dysregulation through an epigenetic impairment of synaptic plasticity within ventral tegmental area (VTA) DA neurons. Using a single 24-hr episode of MD and whole-cell patch clamp recording in rat midbrain slices, we show that MD selectively induces long-term depression (LTD) and shifts spike timing-dependent plasticity (STDP) toward LTD at GABAergic synapses onto VTA DA neurons through epigenetic modifications of postsynaptic scaffolding A-kinase anchoring protein 79/150 (AKAP79/150) signaling. Histone deacetylase (HDAC) inhibition rescues GABAergic metaplasticity and normalizes AKAP signaling in MD animals. MD-induced reversible HDAC-mediated GABAergic dysfunction within the VTA may be a mechanistic link for increased propensity to mental health disorders following MD.
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Authement
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Jayaraj N
authors.initials: JN
authors.lastname: Kodangattil
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Shawn
authors.initials: S
authors.lastname: Gouty
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Milan
authors.initials: M
authors.lastname: Rusnak
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Aviva J
authors.initials: AJ
authors.lastname: Symes
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Cox
authors.affiliation: Department of Pharmacology, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA. Electronic address: fereshteh.nugent@usuhs.edu.
authors.forename: Fereshteh S
authors.initials: FS
authors.lastname: Nugent
mesh_terms: D054758:A Kinase Anchor Proteins / Q000502:physiology*; D000818:Animals; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D059330:GABAergic Neurons / Q000187:drug effects / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D008297:Male; D008426:Maternal Deprivation; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D054758:A Kinase Anchor Proteins; C487775:AKAP5 protein, human; C415703:Akap5 protein, rat; D056572:Histone Deacetylase Inhibitors