title: Adolescent Intermittent Alcohol Exposure: Dysregulation of Thrombospondins and Synapse Formation are Associated with Decreased Neuronal Density in the Adult Hippocampus.
abstract: BACKGROUND
  Adolescent intermittent alcohol exposure (AIE) has profound effects on neuronal function. We have previously shown that AIE causes aberrant hippocampal structure and function that persists into adulthood. However, the possible contributions of astrocytes and their signaling factors remain largely unexplored. We investigated the acute and enduring effects of AIE on astrocytic reactivity and signaling on synaptic expression in the hippocampus, including the impact of the thrombospondin (TSP) family of astrocyte-secreted synaptogenic factors and their neuronal receptor, alpha2delta-1 (α2δ-1). Our hypothesis is that some of the influences of AIE on neuronal function may be secondary to direct effects on astrocytes.
  
  
  METHODS
  We conducted Western blot analysis on TSPs 1 to 4 and α2δ-1 from whole hippocampal lysates 24 hours after the 4th and 10th doses of AIE, then 24 days after the last dose (in adulthood). We used immunohistochemistry to assess astrocyte reactivity (i.e., morphology) and synaptogenesis (i.e., colocalization of pre- and postsynaptic puncta).
  
  
  RESULTS
  Adolescent AIE reduced α2δ-1 expression, and colocalized pre- and postsynaptic puncta after the fourth ethanol (EtOH) dose. By the 10th dose, increased TSP2 levels were accompanied by an increase in colocalized pre- and postsynaptic puncta, while α2δ-1 returned to control levels. Twenty-four days after the last EtOH dose (i.e., adulthood), TSP2, TSP4, and α2δ-1 expression were all elevated. Astrocyte reactivity, indicated by increased astrocytic volume and area, was also observed at that time.
  
  
  CONCLUSIONS
  Repeated EtOH exposure during adolescence results in long-term changes in specific astrocyte signaling proteins and their neuronal synaptogenic receptor. Continued signaling by these traditionally developmental factors in adulthood may represent a compensatory mechanism whereby astrocytes reopen the synaptogenic window and repair lost connectivity, and consequently contribute to the enduring maladaptive structural and functional abnormalities previously observed in the hippocampus after AIE.
authors.affiliation: Durham VA Medical Center, Duke University Medical Center, Durham, North Carolina.|Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
authors.forename: Mary-Louise
authors.initials: ML
authors.lastname: Risher
authors.affiliation: Durham VA Medical Center, Duke University Medical Center, Durham, North Carolina.|Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
authors.forename: Hannah G
authors.initials: HG
authors.lastname: Sexton
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: W Christopher
authors.initials: WC
authors.lastname: Risher
authors.affiliation: Social Sciences Research Institute, Duke University Medical Center, Durham, North Carolina.
authors.forename: Wilkie A
authors.initials: WA
authors.lastname: Wilson
authors.affiliation: Durham VA Medical Center, Duke University Medical Center, Durham, North Carolina.|Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
authors.forename: Rebekah L
authors.initials: RL
authors.lastname: Fleming
authors.affiliation: Durham VA Medical Center, Duke University Medical Center, Durham, North Carolina.|Department of Neurosurgery, Duke University Medical Center, Durham, North Carolina.
authors.forename: Roger D
authors.initials: RD
authors.lastname: Madison
authors.affiliation: Durham VA Medical Center, Duke University Medical Center, Durham, North Carolina.|Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Moore
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Cagla
authors.initials: C
authors.lastname: Eroglu
authors.affiliation: Durham VA Medical Center, Duke University Medical Center, Durham, North Carolina.|Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.|Department of Psychology and Neuroscience, Duke University Medical Center, Durham, North Carolina.
authors.forename: H Scott
authors.initials: HS
authors.lastname: Swartzwelder
mesh_terms: D000367:Age Factors; D000818:Animals; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D019699:Thrombospondins / Q000096:biosynthesis*
chemical_list: D019699:Thrombospondins; D000431:Ethanol
keywords: Adolescence; Astrocytes; Ethanol; Hippocampus; Thrombospondin