title: Maternal Stress Combined with Terbutaline Leads to Comorbid Autistic-Like Behavior and Epilepsy in a Rat Model.
abstract: Human autism is comorbid with epilepsy, yet, little is known about the causes or risk factors leading to this combined neurological syndrome. Although genetic predisposition can play a substantial role, our objective was to investigate whether maternal environmental factors alone could be sufficient. We examined the independent and combined effects of maternal stress and terbutaline (used to arrest preterm labor), autism risk factors in humans, on measures of both autistic-like behavior and epilepsy in Sprague-Dawley rats. Pregnant dams were exposed to mild stress (foot shocks at 1 week intervals) throughout pregnancy. Pups were injected with terbutaline on postnatal days 2-5. Either maternal stress or terbutaline resulted in autistic-like behaviors in offspring (stereotyped/repetitive behaviors and deficits in social interaction or communication), but neither resulted in epilepsy. However, their combination resulted in severe behavioral symptoms, as well as spontaneous recurrent convulsive seizures in 45% and epileptiform spikes in 100%, of the rats. Hippocampal gliosis (GFAP reactivity) was correlated with both abnormal behavior and spontaneous seizures. We conclude that prenatal insults alone can cause comorbid autism and epilepsy but it requires a combination of teratogens to achieve this; testing single teratogens independently and not examining combinatorial effects may fail to reveal key risk factors in humans. Moreover, astrogliosis may be common to both teratogens. This new animal model of combined autism and epilepsy permits the experimental investigation of both the cellular mechanisms and potential intervention strategies for this debilitating comorbid syndrome.
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309, and.
authors.forename: Florencia M
authors.identifier: http://orcid.org/0000-0001-9022-5331
authors.initials: FM
authors.lastname: Bercum
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309, and.
authors.forename: Krista M
authors.initials: KM
authors.lastname: Rodgers
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309, and.
authors.forename: Alex M
authors.initials: AM
authors.lastname: Benison
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309, and.
authors.forename: Zachariah Z
authors.initials: ZZ
authors.lastname: Smith
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309, and.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Taylor
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309, and.
authors.forename: Elise
authors.initials: E
authors.lastname: Kornreich
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309, and.
authors.forename: Heidi L
authors.initials: HL
authors.lastname: Grabenstatter
authors.affiliation: Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, Utah 84108.
authors.forename: F Edward
authors.initials: FE
authors.lastname: Dudek
authors.affiliation: Department of Psychology and Neuroscience, University of Colorado, Boulder, Colorado 80309, and daniel.barth@colorado.edu.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Barth
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001321:Autistic Disorder / Q000209:etiology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000209:etiology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000473:pathology; D006624:Hippocampus / Q000473:pathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D012919:Social Behavior; D013315:Stress, Psychological / Q000503:physiopathology*; D013566:Sympathomimetics / Q000633:toxicity*; D013726:Terbutaline / Q000633:toxicity*; D014828:Vocalization, Animal
chemical_list: D005904:Glial Fibrillary Acidic Protein; D013566:Sympathomimetics; D013726:Terbutaline
keywords: autism; epilepsy; maternal stress; neuroinflammation; terbutaline