Early-Life Stress Perturbs Key Cellular Programs in the Developing XXXX Hippocampus.

@entity1 @entity19 @entity4778 @entity2794 @entity1642
UNASSIGNED: Conflicting reports are available with regard to the effects of childhood abuse and neglect on hippocampal function in @entity1 . While earlier imaging studies and some animal work have suggested that the effects of @entity1642 ( @entity1642 ) manifest only in adulthood, more recent studies have documented impaired hippocampal function in maltreated @entity1 and adolescents. Additional work using animal modes is needed to clarify the effects of @entity1642 on hippocampal development. In this regard, genomic, proteomic, and molecular tools uniquely available in the @entity19 make it a particularly attractive model system to study this issue. However, very little work has been done so far to characterize the effects of @entity1642 on hippocampal development in the @entity19 . To address this issue, we examined the effects of @entity2794 ( @entity2794 ), a @entity19 model of @entity1642 that impairs hippocampal-dependent memory in adulthood, on hippocampal development in 28-day-old juvenile @entity19 . This age was chosen because it corresponds to the developmental period in which @entity1 imaging studies have revealed abnormal hippocampal development in maltreated @entity1 . Exposure to @entity2794 caused a significant decrease in the total protein content of synaptosomes harvested from the hippocampus of 28-day-old male and female @entity19 , suggesting that @entity2794 impairs normal synaptic development in the juvenile hippocampus. Using a novel liquid chromatography multiple reaction monitoring mass spectrometry (LC-MRM) assay, we found decreased expression of many synaptic proteins, as well as proteins involved in axonal growth, myelination, and mitochondrial activity. Golgi staining in 28-day-old @entity2794 @entity19 showed an increase in the number of immature and abnormally shaped spines and a decrease in the number of mature spines in @entity4778 neurons, consistent with defects in synaptic maturation and synaptic pruning at this age. In 14-day-old pups, @entity2794 deceased the expression of proteins involved in axonal growth and myelination, but did not affect the total protein content of synaptosomes harvested from the hippocampus, or protein levels of other synaptic markers. These results add two important findings to previous work in the field. First, our findings demonstrate that in 28-day-old juvenile @entity19 , @entity2794 impairs synaptic maturation and reduces the expression of proteins that are necessary for axonal growth, myelination, and mitochondrial function. Second, the results suggest a sequential model in which @entity2794 impairs normal axonal growth and myelination before it disrupts synaptic maturation in the juvenile hippocampus.
