Early life influences of pharmacological and immune stressors on development

Neurodevelopmental disorders manifest early and may impair function throughout life. Exposure to environmental challenges is thought to play a causal role in many such disorders, but a key unanswered question relates to the vulnerability window(s) during which there is an increased sensitivity to these challenges. In a mouse model, we found that administration of the GABAergic toxicant valproic acid (VPA) differentially disrupted neurobehavioral development depending on the precise timing of exposure, and that the resulting behavioral profiles were sex-dependent. Specifically, neonatal C57BL/6 mice were challenged with 400 mg/kg VPA or saline on postnatal day 14 (P14) or 300 mg/kg VPA or saline on postnatal day 7 (P7). Animals were then assessed on a battery of behavioral tests chosen to assess social, emotional, and cognitive functioning. While VPA exposure at P14 resulted in a behaviorally disinhibited phenotype in males, VPA exposure at P7 resulted in social abnormalities in females. In addition, a single VPA challenge at either P7 or P14 affected dendritic spine plasticity in brain regions thought to regulate behaviors that reflect impulsivity. Finally, the behavioral consequences of VPA challenge were compared with an immunogenic challenge using the T cell superantigen, staphylococcal enterotoxin A (SEA). Challenge with SEA at P7 and P14 revealed that interleukin-2 (IL-2) production was lacking at P7, but not P14. Therefore, behavior was investigated after P14 treatment. There were no major differences in social, emotional or cognitive behaviors between SEA- and saline-treated mice during adolescence or adulthood. Overall, this investigation revealed that pharmacological challenges that focus on disruption of the GABAergic system influenced neurodevelopment in a sex- and time-dependent manner. However, T cell immune challenge was less disruptive, possibly due to the absence of key neuromodulatory cytokines that are normally induced by SEA in adult rodents and by other proinflammatory stimuli that target non-T cell populations. In conclusion, identifying the approximate vulnerability windows during postnatal development may allow for a better understanding of underlying mechanisms resulting in toxicant-induced deficits and provide a focus for prevention efforts.Ph.D.Includes bibliographical reference