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Neuroinflammation and behavioral abnormalities after neonatal terbutaline treatment in rats: implications for autism
M C Zerrate1, M Pletnikov, S L Connors
1Department of Neurology, Pathology 627, 600 N. Wolfe St., Baltimore, MD 21287, USA.
Insights
Early exposure to terbutaline, a medication for preterm labor, in newborn rats caused microglial activation and autism-like behaviors. This suggests prenatal drug exposure may impact neurodevelopment and contribute to autism risk.
Area of Science:
- Neuroscience
- Developmental Biology
- Pharmacology
Background:
- Autism Spectrum Disorder (ASD) is a neurodevelopmental condition characterized by social and communication deficits and repetitive behaviors.
- While genetics play a role, prenatal exposure to certain drugs and chemicals are emerging as potential risk factors for ASD.
- Terbutaline, a beta2-adrenoceptor agonist used to prevent preterm labor, has been linked to increased autism rates in twins.
Purpose of the Study:
- To investigate the impact of terbutaline exposure on microglial activation in developing rat brains.
- To assess the behavioral outcomes in rats following early-life terbutaline administration.
- To explore the potential link between terbutaline, neuroinflammation, and autism spectrum disorder-like phenotypes.
Main Methods:
- Newborn rats received daily terbutaline (10 mg/kg) on postnatal days 2-5 or 11-14.
- Microglial activation was assessed using immunohistochemistry at postnatal day 30.
- Behavioral tests, including open field and acoustic startle response, were conducted to evaluate responses to stimuli.
Main Results:
- Terbutaline administration on postnatal days 2-5 led to significant microglial activation in the cerebral cortex, cerebellar white matter, and cerebrocortical white matter by postnatal day 30.
- No significant microglial activation was observed when terbutaline was given on postnatal days 11-14.
- Rats treated with terbutaline on postnatal days 2-5 exhibited hyper-reactivity to novelty and aversive stimuli in behavioral tests.
Conclusions:
- Early-life overstimulation of beta2-adrenoceptors by terbutaline during a critical developmental window can induce microglial activation.
- This neuroinflammatory response is associated with behavioral abnormalities resembling those seen in autism spectrum disorder.
- The study provides a valuable animal model for investigating the neuropathological mechanisms underlying autism spectrum disorder and the role of prenatal exposures.
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 beta2-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 beta2-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.
