Early Life Stress Inhibits Expression of a Novel Innate Immune Pathway in the Developing Hippocampus

Abstract

Childhood maltreatment represents a major risk factor for the development of numerous childhood psychopathologies that in many cases linger as chronic mental illnesses in adulthood. Exposing rodents or non-human primates to early life stress increases anxiety-like behaviors and impairs cognitive function in adulthood, suggesting that animal models may provide important insights into parallel developmental processes in humans. Using an unbiased genomic screen, we found that expression of lipopolysaccharide binding protein (LBP), a member of the innate immune system, is dramatically decreased in the hippocampus of pups exposed to early life stress. LBP levels peak in the normally developing hippocampus at a period of intense synaptic pruning, during which LBP is colocalized with the synaptic marker PSD95 and is found in close proximity to processes of microglia cells. Expression of LBP declines to low levels seen in adulthood at around postnatal day 30. Importantly, 30-day-old LBP knockout (k.o.) mice show increased spine density and abnormal spine morphology, suggesting that peak levels of LBP during the second and third weeks of life are necessary for normal synaptic pruning in the hippocampus. Finally, LBP k.o. mice show impaired hippocampal-dependent memory and increased anxiety-like behaviors in a manner that resembles that seen in animals exposed to early life stress. These findings describe a novel role for LBP in normal hippocampal development and raise the possibility that at least some of the behavioral sequelae of early life stress are mediated by reduced expression of LBP during a critical period of neurodevelopment.

Maternal separation induces hippocampal changes in cadherin-1 (CDH-1) mRNA and recognition memory impairment in adolescent mice

“…The specific statistical tests are given in the results section and/or appropriate figure legends. Regarding our sample size, they are similar to others molecular and behavioral reports (Gapp et al, 2014;Kundakovic et al, 2013;Viola et al, 2016;Wei, Simen, Mane, & Kaffman, 2012). All data are presented as group mean ± standard error of the mean (SEM).…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Physiological synaptic pruning by microglia appear to be triggered by the expression of lipopolysaccharidebinding protein and the synaptic marker protein PSD-95 in the microglia. Decreases in the availability of these two key proteins in the microglia were noticed both in animals exposed to early life stress and prenatal infections, and the loss of these proteins was associated with aberrant synaptogenesis, deficient glutamate neurotransmission, and impaired cognitive performance (Durieux et al, 2015;Wei et al, 2012).…”

Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma?

“…In pups, at a time when brain development is taking place (Box 2), maternal separation was found to be associated with blunted expression of pro-inflammatory mediators (lipopolysaccharide-binding protein) in the hippocampus (Wei et al, 2012) and with reduced microglial cell number in midbrain areas (Chocyk et al, 2011). In contrast, in adult animals, early maternal separation was associated with greater synaptic levels of the receptor for the pro-inflammatory cytokine interleukin-1 (IL-1) (Viviani et al, 2014),…”