Identifying a role for glial cells in the development of affective disorders: Early-life differences in hippocampal gene expression in selectively bred rats
Maras PM, Blandino P, Hebda-Bauer EK, Watson SJ, Akil H
Society for Neuroscience. 2017.
The development of many emotional disorders is strongly influenced by genetic factors. Using rats that have been selectively bred for their locomotor response to a novel environment, we have developed two contrasting genetic backgrounds that differ in emotional temperament: rats bred for high locomotor responses (bHRs) exhibit low spontaneous anxiety and are resilient to depression, whereas rats bred for low locomotor responses (bLRs) are highly anxious and vulnerable to depression. Importantly, we can predict adult behavioral phenotype based on lineage with almost 100% certainty and can therefore use this model to identify key developmental factors that may precede emotional dysfunction. Among the possible factors, a growing body of evidence indicates that supportive cells of the brain, including astrocytes, microglia, and oligodendrocytes, play a critical role in shaping normal brain development, and glial dysfunction may underlie many affective disorders. The exact mechanisms by which glial cells organize emotional brain circuits and ultimately determine affective behaviors, however, remain unclear. Thus, the current set of experiments examined early postnatal expression of several glial-related genes in the bHRs/bLRs model. Hippocampal tissue samples were collected from 14-day old bHR and bLR pups, and relative mRNA levels were measured using quantitative real-time PCR. Already at this young age, robust differences in glial gene expression were evident: compared to bHRs, bLRs expressed a) higher levels of microglial markers and pro-inflammatory cytokines, b) lower levels of astrocyte-specific excitatory amino acid transporters, and c) lower levels of key myelin-related genes. Taken together, these studies reveal broad differences in an array of glial genes, such that the emotionally vulnerable bLRs appear to have elevated microglia activation and reduced astrocyte and oligodendrocyte function during a critical window of hippocampal development. Moreover, these results suggest that glial dysfunction per se may reflect an early factor that drives the development of affective disorders. Ongoing studies are now examining whether pharmacologically manipulating glial function during this early-life period alters the bHR/bLR phenotype, as well as the organization of the hippocampus.