Abstract
BackgroundAutism spectrum disorder (ASD) affects many children and juveniles. The pathogenesis of ASD is not well understood. Environmental factors may play important roles in the development of ASD. We examined a possible relationship of inflammatory pain in neonates and the development of ASD in juveniles.MethodsAcute inflammation pain was induced by 5 % formalin (5 μl/day) subcutaneous injection into two hindpaws of postnatal day 3 to 5 (P3–P5) rat pups. Western blot, immunohistochemical, and behavioral examinations were performed at different time points after the insult.ResultsFormalin injection caused acute and chronic inflammatory responses including transient local edema, increased levels of inflammatory cytokines, TNF-α, and IL-1β in the blood as well as in the brain, and increased microglia in the brain. One day after the pain insult, there was significant cell death in the cortex and hippocampus. Two weeks later, although the hindpaw local reaction subsided, impaired axonal growth and demyelization were seen in the brain of P21 juvenile rats. The number of bromodeoxyuridine (BrdU) and doublecortin (DCX) double-positive cells in the hippocampal dentate gyrus of P21 rats was significantly lower than that in controls, indicating reduced neurogenesis. In the P21 rat’s brain of the formalin group, the expression of autism-related gene neurexin 1 (NRXN1), fragile X mental retardation 1 (FMR1), and oxytocin was significantly downregulated, consistent with the gene alteration in ASD. Juvenile rats in the formalin group showed hyperalgesia, repetitive behaviors, abnormal locomotion, sleep disorder, and distinct deficits in social memory and social activities. These alterations in neuroinflammatory reactions, gene expression, and behaviors were more evident in male than in female rats. Importantly, an anti-inflammation treatment using indomethacin (10 mg/kg, i.p.) at the time of formalin injections suppressed inflammatory responses and neuronal cell death and prevented alterations in ASD-related genes and the development of abnormal behaviors.ConclusionsThese novel observations indicate that severe inflammatory pain in neonates and persistent inflammatory reactions may predispose premature infants to development delays and psychiatric disorders including ASD. The prevention of pain stimuli and prompt treatments of inflammation during development appear vitally important in disrupting possible evolution of ASD syndromes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0575-x) contains supplementary material, which is available to authorized users.
Highlights
Autism spectrum disorder (ASD) affects many children and juveniles
Local reactions of formalin-induced peripheral inflammatory pain in neonatal rats Subcutaneous injection of 5 μl 5 % formalin or saline was applied to right and left hindpaws of postnatal day 3 (P3) rats, followed by two additional injections at postnatal days 4 and 5, respectively
These repeated injections were to mimic acute insults experienced by human premature babies subjected to multiple procedures in neonatal intensive care unit (NICU)
Summary
Autism spectrum disorder (ASD) affects many children and juveniles. Preterm infants are at increased risk for developmental disorders, abnormal behaviors, and cognitive dysfunction syndromes that can be associated with autism spectrum disorder (ASD) [2, 3]. According to the recent guideline of American Psychiatric Association (APA), clinical diagnostic criteria include the following: (a) persistent deficits in social communication and social interaction across multiple contexts; (b) Restricted, repetitive patterns of behavior, interests, or activities; (c) symptoms must be present in the early developmental period; (d) symptoms cause clinically significant impairment in social, occupational, or other important areas of current functioning; and (e) these disturbances are not better explained by intellectual disability (intellectual developmental disorder) or global developmental delay [9]. We used the term autism spectrum disorder or ASD to refer to autism-like behaviors in the animal model tested in this investigation
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