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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Department of Neurology (M.C.Z., D.L.V., A.W.Z., C.A.P.), Neuroimmunopathology Laboratory (M.C.Z., D.L.V., C.A.P.), and Pathology (C.A.P.), and Department of Psychiatry and Behavioral Sciences (M.P., A.W.Z.), Johns Hopkins University School of Medicine, Baltimore, Maryland; Kennedy Krieger Institute (A.W.Z., S.L.C.), Baltimore, Maryland; and Department of Pharmacology and Cancer Biology (F.J.S., T.A.S.), and Psychiatry and Behavioral Sciences (T.A.S.), Duke University Medical Center, Durham, North Carolina

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.

Address correspondence to: Dr. Carlos A. Pardo, Department of Neurology, Pathology 627, 600 N. Wolfe St., Baltimore, MD 21287. E-mail: cpardo{at}jhmi.edu