Neuroinflammation and Behavioral Abnormalities after Neonatal Terbutaline Treatment in Rats: Implications for Autism

Abstract

Autism is a neurodevelopmental disorder presenting before 3 years of age with deficits in communication and social skills and repetitive behaviors. In addition to genetic influences, recent studies suggest that prenatal drug or chemical exposures are risk factors for autism. Terbutaline, a ␤2-adrenoceptor agonist used to arrest preterm labor, has been associated with increased concordance for autism in dizygotic twins. We studied the effects of terbutaline on microglial activation in different brain regions and behavioral outcomes in developing rats. Newborn rats were given terbutaline (10 mg/kg) daily on postnatal days (PN) 2 to 5 or PN 11 to 14 and examined 24 h after the last dose and at PN 30. Immunohistochemical studies showed that administration of terbutaline on PN 2 to 5 produced a robust increase in microglial activation on PN 30 in the cerebral cortex, as well as in cerebellar and cerebrocortical white matter. None of these effects occurred in animals given terbutaline on PN 11 to 14. In behavioral tests, animals treated with terbutaline on PN 2 to 5 showed consistent patterns of hyper-reactivity to novelty and aversive stimuli when assessed in a novel open field, as well as in the acoustic startle response test. Our findings indicate that ␤2-adrenoceptor overstimulation during an early critical period results in microglial activation associated with innate neuroinflammatory pathways and behavioral abnormalities, similar to those described in autism. This study provides a useful animal model for understanding the neuropathological processes underlying autism spectrum disorders.

Autism genes are selectively targeted by environmental pollutants including pesticides, heavy metals, bisphenol A, phthalates and many others in food, cosmetics or household products

“…Newborn rats treated with terbutaline (10 mg/kg) daily on postnatal days 2 to 5 or PN 11 to 14 showed a robust increase in microglial activation on postnatal day 30 in the cerebral cortex, as well and in cerebellar and cerebrocortical white matter. hyper-reactivity to novelty and aversive stimuli was also observed [126]. Oxytocin Labour induction or augmented labour associated with an increased risk of subsequent autism (exogenous oxytocin and prostaglandins) [127].…”

A Novel Rodent Model of Autism: Intraventricular Infusions of Propionic Acid Increase Locomotor Activity and Induce Neuroinflammation and Oxidative Stress in Discrete Regions of Adult Rat Brain

“…There has been growing interest in a group of environmental toxins and infectious agents which could act at critical periods of pre-and post-natal development to putatively trigger or exacerbate this disorder in genetically vulnerable individuals. An increased risk of ASD is associated with pre-natal exposure to ethanol [22] , valproic acid [23] , terbutaline [24] , some metals and viral infections [25,26] . Many of these effects have been observed in animal models using these toxic or infectious agents.…”

Does Treatment of Premature Labor With Terbutaline Increase the Risk of Autism Spectrum Disorders?

“…However, subsequent to the publication of the article by Vargas et and white matter of cortex and cerebellum in terbutaline-exposed rats. 25 The meaning of these results is not clear because gliosis is not a finding that is restricted to autism.…”