An Early-Life Infection with Escherichia coli in BALB/c Mice causes Long-Lasting Deficits in Behavior, Brain Development, and Microglial Reactivity.

摘要

There is mounting evidence that inflammatory insults that occur early in life can significantly influence normal brain development and promote neurobehavioral deficits that manifest in young adulthood. The biochemical mechanisms underlying these complications, however, are poorly understood. We developed a model of early-life infection in BALB/c mice using a peripheral injection of Escherichia coli in neonatal mice. This transient infection had a profound influence on behavioral phenotype, brain development, and response to a secondary immune challenge later in young adulthood. For instance, early-life infected mice had impaired motor coordination and hyperactivity that was evident 1 and 2 months after the neonatal infection. In addition, these behavioral deficits were associated with hypomyelination in the subcortical white matter, cortex, and hippocampus. Hypomyelination was concomitant with a reduced number of oligodendrocytes in the subcortical white matter and a robust increase in L-ferritin in the brain of early-life infected mice that localized to the cytoplasm of neurons. Early-life infection also promoted microglial priming resulting in hyperactivation of these cells following a secondary immune challenge. Exaggerated inflammatory cytokine production corresponded to increased Iba1 immunoreactivity of microglia specifically in the amygdala and hippocampus of ELI mice 48 hours following LPS. Taken together, these data indicate that a peripheral infection during neonatal brain development promotes abnormal iron storage in neurons, reduces oligodendrocytes, markedly impairs myelination, and primes microglia. These biochemical changes corresponded to long lasting deficits in behavior and motor coordination. Understanding the biochemical and immune complications that result from an early-life insult will provide new therapeutic targets to attenuate neurobehavioral complications, such as attention deficit disorder, autism, and schizophrenia.