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.

Comorbid epilepsy in autism spectrum disorder: Implications of postnatal inflammation for brain excitability

“…This mouse model of comorbid ASD and epilepsy is facilitated if BTBR mice are exposed to inflammation during an early stage of life, which incorporates an environmental “second hit” into the model. Interestingly, a recent study found that in the maternal immune activation model of ASD, a drug treatment (ie, terbutaline) in the offspring in the early neonatal period also was required for the appearance of comorbid ASD and epilepsy . Converging evidence from this study and ours indicates that early life events may induce physiological alterations that lead to chronic seizure susceptibility and epileptogenesis in rodent models of ASD.…”

“…Interestingly, a recent study found that in the maternal immune activation model of ASD, a drug treatment (ie, terbutaline) in the offspring in the early neonatal period also was required for the appearance of comorbid ASD and epilepsy. 40 Converging evidence from this study and ours indicates that early life events may induce physiological alterations that lead to chronic seizure susceptibility and epileptogenesis in rodent models of ASD. Given that human infants, unlike our research animals, grow up in an environment replete with pharmacological, immune, and behavioral stressors, it is likely that mouse models with both face and construct validity that incorporate these events will be required to investigate underlying mechanisms of ASD and epilepsy comorbidity.…”

Emerging Roles for the Gut Microbiome in Autism Spectrum Disorder

“…In addition to the spectrum of behavioral abnormalities in ASD, several medical comorbidities are also observed in ASD individuals, ranging from seizures and anxiety to sleep deficiency and metabolic impairments (1–5). Brain changes in ASD include a reported 67% more neurons in the prefrontal cortex, more than 17% increase in brain weight, and abnormal cortical patterning.…”

Neurobehavioral comorbidities of epilepsy: Role of inflammation

“…It is possible that expression of both epilepsy and ASD may require coordinated action of more than one precipitating factor and that this is lacking in these models. For example, a recent study showed that imposition of maternal stress plus terbutaline (a ß2‐adrenoreceptor agonist used to prevent preterm labor) resulted in emergence of an epilepsy–ASD phenotype, although neither intervention by itself was effective . We have explored the possibility that an additional stressor that elevates CNS cytokines may facilitate emergence of an epilepsy phenotype in the BTBR mouse.…”