title: In utero exposure to valproic acid changes sleep in juvenile rats: a model for sleep disturbances in autism.
abstract: OBJECTIVE
  To determine whether sleep disturbances are found in the valproic acid model of autism spectrum disorders (ASD).
  
  
  METHODS
  Comparative study for sleep behavior, sleep architecture, electroencephalogram (EEG) spectral analysis, and glutamic acid decarboxylase (GAD) 65/67 protein expression in juvenile rats exposed to valproic acid (VPA), sodium salt, or saline in utero.
  
  
  METHODS
  N/A.
  
  
  METHODS
  Juvenile (postnatal day 32) male and female Sprague-Dawley rats.
  
  
  METHODS
  In utero exposure to either saline or 400 mg/kg VPA administered intraperitoneally to the dams on gestational day 12.5. On postnatal days 22-24, all rats were implanted with transmitters to record EEG and electromyogram (EMG) activity.
  
  
  RESULTS
  During the light phase, when nocturnal animals are typically quiescent, the VPA-exposed animals spent significantly more time in wake (∼35 min) and significantly less time in non-rapid eye movement (NREM) sleep (∼26 min) compared to the saline controls. Furthermore, spectral analysis of the EEG revelled that VPA-exposed animals exhibited increased high-frequency activity during wake and rapid eye movement (REM) sleep and reduced theta power across all vigilance states. Interestingly, the gamma-aminobutyric acid (GABA)-ergic system, which modulates the induction and maintenance of sleep states, was also disrupted, with reduced levels of both GAD 65 and GAD67 in the cortical tissue of VPA-exposed animals compared to saline controls.
  
  
  CONCLUSIONS
  To date, the current animal models of ASD have been underutilized in the investigation of associated sleep disturbances. The VPA animal model recapitulates aspects of sleep disruptions reported clinically, providing a tool to investigate cellular and molecular dysregulation contributing to sleep disruptions in ASD.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Cusmano
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Mong
mesh_terms: D000375:Aging; D000818:Animals; D001143:Arousal / Q000187:drug effects; D002659:Child Development Disorders, Pervasive / Q000150:complications* / Q000503:physiopathology; D002940:Circadian Rhythm; D004195:Disease Models, Animal; D004569:Electroencephalography; D004576:Electromyography; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism; D008297:Male; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000187:drug effects* / Q000502:physiology; D012893:Sleep Wake Disorders / Q000139:chemically induced* / Q000150:complications* / Q000503:physiopathology; D012895:Sleep, REM / Q000187:drug effects; D014599:Uterus; D014635:Valproic Acid / Q000008:administration & dosage* / Q000494:pharmacology*; D014851:Wakefulness / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D005680:gamma-Aminobutyric Acid; D014635:Valproic Acid
keywords: autism spectrum disorders; sleep; valproic acid